Is MYO7A p.Thr1729Met (c.5186C>T) pathogenic?

MYO7A p.Thr1729Met (c.5186C>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.8149); Ultra-rare (popmax 0.0342%, eas); Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Thr1729Met (c.5186C>T)?

MYO7A p.Thr1729Met (c.5186C>T) is associated with autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, autosomal dominant nonsyndromic hearing loss 11 (ClinVar).

How common is MYO7A p.Thr1729Met (c.5186C>T) in the general population?

MYO7A p.Thr1729Met (c.5186C>T) is ultra-rare (popmax 0.0342%, eas) (gnomAD).

What do computational predictors say about MYO7A p.Thr1729Met (c.5186C>T)?

AlphaMissense predicts likely pathogenic (score 0.8149) — an in-silico prediction, not a clinical call.

MYO7A p.Thr1729Met

c.5186C>T · rs1367144630 · VCV883236

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0342%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.8149	likely pathogenic
REVEL	0.518	indeterminate
SaProt	LLR -7.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.5	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 0.0342% East Asian · 14/40,928 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0165%

Overall 0.00181% 28/1,548,030 alleles · ultra-rare exomes 21/1,395,814 · genomes 7/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0342%	2,923
African / African-American	0.00959%	10,425
Remaining individualsnot grpmax-eligible	0.00167%	59,884
European (non-Finnish)	0.000523%	191,125

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.Thr1729Met
Coding: c.5186C>T
MANE Select: NM_000260
dbSNP: rs1367144630
Type: single nucleotide variant
Location: chr11:77203077 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1729: a turn

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 autosomal dominant nonsyndromic hearing loss 11

Similar variants

MYO7A p.Thr1729Arg Uncertain significance ★ ⚠ same residue
MYO7A p.Thr1729= 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
MYO7A p.Arg853His 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-thr1729met (accessed [today's date]).

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