Is MYO7A p.Arg606His (c.1817G>A) pathogenic?

MYO7A p.Arg606His (c.1817G>A) is classified Uncertain significance in MYO7A (ClinVar, Expert panel, 7 submitters; last evaluated 2023-07-19). AlphaMissense: likely pathogenic (0.7869); Ultra-rare (popmax 0.0356%, sas); Associated with nonsyndromic genetic hearing loss.

What condition is associated with MYO7A p.Arg606His (c.1817G>A)?

MYO7A p.Arg606His (c.1817G>A) is associated with nonsyndromic genetic hearing loss, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg606His (c.1817G>A) in the general population?

MYO7A p.Arg606His (c.1817G>A) is ultra-rare (popmax 0.0356%, 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.Arg606His (c.1817G>A)?

AlphaMissense predicts likely pathogenic (score 0.7869) — an in-silico prediction, not a clinical call.

MYO7A p.Arg606His

c.1817G>A · rs782311929 · VCV517357

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7869 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

Uncertain Significance for nonsyndromic genetic deafness. Applied ACMG criteria (verbatim):

PP3 PM3

Curation rationale (ClinGen, verbatim)

The c.1817 G>A (NM_000260.4(MYO7A):c.1817G>A (p.Arg606His)) variant in MYO7A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 606. The highest major allele frequency in gnomAD v2.1.1 is 0.00035 (0.035 % or 8/23092 alleles) in the South Asian population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.832, (which is above the threshold of 0.7), evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least one individual with autosomal recessive nonsyndromic genetic hearing loss. This proband was compound heterozygous for the variant and a pathogenic variant, confirmed in trans by parental testing (PM3; 1.0 point; LMM Internal Data). The patient with this variant displayed moderate to severe sensorineural hearing loss, although no vision anomalies or difficulty seeing at night were noted (PP4 not met; LMM Internal Data). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive nonsyndromic genetic deafness, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PP3, PM3; Version 2, 7.19.2023).

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

Computational evidence

Protein change
AlphaMissense	0.7869	likely pathogenic
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -10.83	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 8.6	GERP -0.43, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0356% South Asian · 30/84,330 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00494% 77/1,558,530 alleles · ultra-rare exomes 72/1,406,332 · genomes 5/152,198 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0356%	2,811
East Asian	0.00484%	20,664
European (non-Finnish)	0.00373%	26,789
Remaining individualsnot grpmax-eligible	0.00166%	60,376
African / African-American	0.00136%	73,306

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.Arg606His
Coding: c.1817G>A
MANE Select: NM_000260
dbSNP: rs782311929
Type: single nucleotide variant
Location: chr11:77172767 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 606: 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: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 2 autosomal dominant nonsyndromic hearing loss 11 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.Arg606Cys Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg606Leu Uncertain significance ★ ⚠ same residue
MYO7A p.Arg606Pro Uncertain significance ★ ⚠ same residue
MYO7A p.Arg606= Likely benign ★ same residue
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

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-arg606his (accessed [today's date]).

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