Is MYO7A p.Arg616Trp (c.1846C>T) pathogenic?

MYO7A p.Arg616Trp (c.1846C>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-09-11). AlphaMissense: likely pathogenic (0.8448); Ultra-rare (popmax 0.0371%, nfe); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Arg616Trp (c.1846C>T)?

MYO7A p.Arg616Trp (c.1846C>T) is associated with MYO7A-related disorder, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg616Trp (c.1846C>T) in the general population?

MYO7A p.Arg616Trp (c.1846C>T) is ultra-rare (popmax 0.0371%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Arg616Trp (c.1846C>T)?

AlphaMissense predicts likely pathogenic (score 0.8448) — an in-silico prediction, not a clinical call.

MYO7A p.Arg616Trp

c.1846C>T · rs369195493 · VCV43160

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.8448 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0371%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.8448	likely pathogenic
REVEL	0.704	pathogenic-leaning
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	27.8	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 0.0371% European (non-Finnish) · 427/1,151,768 alleles

Filtering AF 0.0341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0329%

Overall 0.0298% 464/1,558,958 alleles · ultra-rare exomes 437/1,406,720 · genomes 27/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0371%	2,697
Remaining individualsnot grpmax-eligible	0.0182%	5,494
African / African-American	0.0164%	6,112
South Asian	0.00949%	10,538
Admixed American	0.00769%	13,010
East Asian	0.00242%	41,360
Finnishnot grpmax-eligible	0.00166%	60,070

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.Arg616Trp
Coding: c.1846C>T
MANE Select: NM_000260
dbSNP: rs369195493
Type: single nucleotide variant
Location: chr11:77172796 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 616: the myosin motor domain

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

Disease context

MYO7A-related disorder

Also linked: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 2 autosomal dominant nonsyndromic hearing loss 11 inherited retinal dystrophy Usher syndrome type 1B

Similar variants

MYO7A p.Arg616Gln Conflicting classifications of pathogenicity ★ same residue
MYO7A p.Arg616Leu Uncertain significance ⚠ same residue
MYO7A p.Arg616= 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
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-arg616trp (accessed [today's date]).

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