Is MYO7A p.Thr1496Lys (c.4487C>A) pathogenic?

MYO7A p.Thr1496Lys (c.4487C>A) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-05). AlphaMissense: likely pathogenic (0.7448); Very rare (popmax 8.48e-05%, nfe); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Thr1496Lys (c.4487C>A)?

MYO7A p.Thr1496Lys (c.4487C>A) is associated with MYO7A-related disorder (ClinVar).

How common is MYO7A p.Thr1496Lys (c.4487C>A) in the general population?

MYO7A p.Thr1496Lys (c.4487C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Thr1496Lys (c.4487C>A)?

AlphaMissense predicts likely pathogenic (score 0.7448) — an in-silico prediction, not a clinical call.

MYO7A p.Thr1496Lys

c.4487C>A · VCV3721075

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7448 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.7448	likely pathogenic
REVEL	0.662	pathogenic-leaning
SaProt	LLR -8.41	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 2.2	GERP 0.66, phastCons 0.97
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	24.2	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 8.48e-05% European (non-Finnish) · 1/1,179,896 alleles

Overall 6.2e-05% 1/1,613,914 alleles · very rare exomes 1/1,461,586 · genomes 0/152,328 · joint denominator

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.Thr1496Lys
Coding: c.4487C>A
MANE Select: NM_000260
Type: single nucleotide variant
Location: chr11:77198540 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1496: the ferm 1 domain

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

Disease context

MYO7A-related disorder

Similar variants

MYO7A p.Thr1496Met Uncertain significance ★★ ⚠ same residue
MYO7A p.Thr1496= Conflicting classifications of pathogenicity ★ same residue
MYO7A c.133-2A>G Pathogenic ★★ same condition
MYO7A c.1344-2A>G Pathogenic ★★ same condition
MYO7A c.1690+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.18+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.19-1G>A Likely pathogenic ★★ same condition
MYO7A c.2187+1G>A Pathogenic/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-thr1496lys (accessed [today's date]).

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