Is MYO7A p.Thr165Met (c.494C>T) pathogenic?

MYO7A p.Thr165Met (c.494C>T) is classified Pathogenic/Likely pathogenic in MYO7A (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.9569); Very rare (popmax 0.00267%, afr); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Thr165Met (c.494C>T)?

MYO7A p.Thr165Met (c.494C>T) is associated with MYO7A-related disorder, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Thr165Met (c.494C>T) in the general population?

MYO7A p.Thr165Met (c.494C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MYO7A p.Thr165Met (c.494C>T)?

AlphaMissense predicts likely pathogenic (score 0.9569) — an in-silico prediction, not a clinical call.

MYO7A p.Thr165Met

c.494C>T · rs111033174 · VCV43264

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.9569	likely pathogenic ✓ concordant with ClinVar
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -15.62	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	29.3	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 0.00267% African / African-American · 2/74,912 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00217% 35/1,613,798 alleles · very rare exomes 33/1,461,668 · genomes 2/152,130 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,456
European (non-Finnish)	0.00254%	39,330
South Asian	0.0022%	45,537
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Thr165Met
Coding: c.494C>T
MANE Select: NM_000260
dbSNP: rs111033174
Type: single nucleotide variant
Location: chr11:77156683 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 165: the myosin motor domain; a binding site; a UniProt-annotated variant site (in ush1b)

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.Thr165Ala Likely pathogenic ★ same residue
MYO7A p.Thr165= Conflicting classifications of pathogenicity ★ same residue
MYO7A p.Thr165Lys 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-thr165met (accessed [today's date]).

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