Is MYO7A p.Arg853His (c.2558G>A) pathogenic?

MYO7A p.Arg853His (c.2558G>A) is classified Likely pathogenic in MYO7A (ClinVar, Expert panel, 15 submitters; last evaluated 2022-10-31). AlphaMissense: ambiguous (0.3623); Very rare (popmax 0.00246%, eas); Associated with nonsyndromic genetic hearing loss.

What condition is associated with MYO7A p.Arg853His (c.2558G>A)?

MYO7A p.Arg853His (c.2558G>A) is associated with nonsyndromic genetic hearing loss, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg853His (c.2558G>A) in the general population?

MYO7A p.Arg853His (c.2558G>A) is very rare (popmax 0.00246%, eas) (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.Arg853His (c.2558G>A)?

AlphaMissense predicts ambiguous (score 0.3623) — an in-silico prediction, not a clinical call.

MYO7A p.Arg853His

c.2558G>A · rs111033437 · VCV43186

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

AlphaMissense

ambiguous

0.3623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

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

PP1_Strong PM2_Supporting PS4_Supporting PP3

Curation rationale (ClinGen, verbatim)

The c.2558G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 853. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been reported in 3 probands/families with hearing loss (PS4_Supporting; PMIDs: 26969326, 32097363, ClinVar SCV: SCV000059742.6, LMM). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 10 affected family members from 1 family (PP1_Strong; PMID: 32097363). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PS4_P, PM2_P, PP3 (Hearing Loss VCEP specifications version 2; 10/31/2022).

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

Computational evidence

Protein change
AlphaMissense	0.3623	ambiguous
REVEL	0.741	pathogenic-leaning
SaProt	LLR -12.91	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	28.5	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 0.00246% East Asian · 1/40,686 alleles

Filtering AF 0.000371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000269%

Overall 0.000718% 11/1,531,882 alleles · very rare exomes 10/1,379,648 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00246%	40,686
Remaining individualsnot grpmax-eligible	0.00168%	59,414
European (non-Finnish)	0.000788%	126,880

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.Arg853His
Coding: c.2558G>A
MANE Select: NM_000260
dbSNP: rs111033437
Type: single nucleotide variant
Location: chr11:77179925 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 853: the iq 5 domain; a UniProt-annotated variant site (in dfna11; disturb calmodulin/myo7a binding)

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.Arg853Cys Pathogenic/Likely pathogenic ★★ same residue
MYO7A p.Arg853Ser Likely pathogenic ★ same residue
MYO7A p.Arg853Leu Uncertain significance ★ ⚠ 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
MYO7A p.Arg668Cys 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-arg853his (accessed [today's date]).

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