Is MYO7A p.Arg1347Ser (c.4039C>A) pathogenic?

MYO7A p.Arg1347Ser (c.4039C>A) is classified Uncertain significance in MYO7A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-05-15). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Arg1347Ser (c.4039C>A)?

MYO7A p.Arg1347Ser (c.4039C>A) is associated with autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1 (ClinVar).

How common is MYO7A p.Arg1347Ser (c.4039C>A) in the general population?

MYO7A p.Arg1347Ser (c.4039C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MYO7A p.Arg1347Ser (c.4039C>A)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1347Ser

c.4039C>A · rs111534474 · VCV551762

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 1% in MYO7A
REVEL	0.957	strongly pathogenic-leaning
SaProt	LLR -13.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MYO7A
Protein: p.Arg1347Ser
Coding: c.4039C>A
MANE Select: NM_000260
dbSNP: rs111534474
Type: single nucleotide variant
Location: chr11:77192165 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1347: the ferm 1 domain; a UniProt-annotated variant site (in ush1b)

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

Disease context

autosomal recessive nonsyndromic hearing loss 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1

Similar variants

MYO7A p.Arg1347Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MYO7A p.Arg1347Gly Likely pathogenic ★ same residue
MYO7A p.Arg1347His Conflicting classifications of pathogenicity ★ ⚠ same residue
MYO7A p.Arg1347= 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-arg1347ser (accessed [today's date]).

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