Is MYO7A p.Ser617Pro (c.1849T>C) pathogenic?

MYO7A p.Ser617Pro (c.1849T>C) is classified Likely pathogenic in MYO7A (ClinVar, Expert panel, 9 submitters; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.9992); Very rare (popmax 0.0095%, sas); Associated with nonsyndromic genetic hearing loss.

What condition is associated with MYO7A p.Ser617Pro (c.1849T>C)?

MYO7A p.Ser617Pro (c.1849T>C) is associated with nonsyndromic genetic hearing loss, Meniere disease, Usher syndrome type 1 (ClinVar).

How common is MYO7A p.Ser617Pro (c.1849T>C) in the general population?

MYO7A p.Ser617Pro (c.1849T>C) is very rare (popmax 0.0095%, sas) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MYO7A p.Ser617Pro (c.1849T>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

MYO7A p.Ser617Pro

c.1849T>C · rs782063761 · VCV438172

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0095%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

Likely Pathogenic for nonsyndromic genetic deafness. Applied ACMG criteria (verbatim):

PP1_Strong PP3 PM3

Curation rationale (ClinGen, verbatim)

The c.1849T>C variant in MYO7A is a missense variant predicted to cause substitution of serine by proline at amino acid 617 (p.Ser617Pro). The highest population minor allele frequency in gnomAD v4 is 0.00009496 (8/84244 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with nonsyndromic hearing loss. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by parental testing (c.20G>T [p.Gly7Val], c.1258A>T [p.K420*], 2 PM3 points, PMIDs: 30303587, 33187236). One individual was homozygous for the variant (0.5 PM3 points, PMIDs: 27344577, 33671976) (PM3). The variant has been reported to segregate with nonsyndromic hearing loss in 7 affected family members from 3 families (PP1_Strong; PMIDs: 27344577, 30303587, 33187236, 33671976). This variant has also been detected in 1 individual with Usher syndrome, with a second variant c.4838delA (p.Asp1613ValfsTer32) without phase confirmation (PMIDs: 28041643, 32581362). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PM3, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024). As cases have been observed with both nonsyndromic hearing loss and Usher syndrome and genotype-phenotype correlation is currently unclear, individuals should be evaluated for both conditions.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic ✓ concordant with ClinVar · top 1% in MYO7A
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -11.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0095% South Asian · 8/84,244 alleles

Filtering AF 0.00467% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00344%

Overall 0.000514% 8/1,557,600 alleles · very rare exomes 6/1,405,520 · genomes 2/152,080 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYO7A
Protein: p.Ser617Pro
Coding: c.1849T>C
MANE Select: NM_000260
dbSNP: rs782063761
Type: single nucleotide variant
Location: chr11:77172799 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 617: the myosin motor domain

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nonsyndromic genetic hearing loss — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meniere disease Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 2 Usher syndrome hearing loss, autosomal recessive Usher syndrome type 1B

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition
MYO7A p.Arg853His Likely pathogenic ★★★ same condition
MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Gly2187Asp Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-ser617pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown