Is MYO7A p.Asp1399His (c.4195G>C) pathogenic?

MYO7A p.Asp1399His (c.4195G>C) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-03-02). AlphaMissense: likely pathogenic (0.9501); Ultra-rare (popmax 0.0107%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MYO7A p.Asp1399His (c.4195G>C)?

MYO7A p.Asp1399His (c.4195G>C) is associated with Inborn genetic diseases, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Asp1399His (c.4195G>C) in the general population?

MYO7A p.Asp1399His (c.4195G>C) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Asp1399His (c.4195G>C)?

AlphaMissense predicts likely pathogenic (score 0.9501) — an in-silico prediction, not a clinical call.

MYO7A p.Asp1399His

c.4195G>C · rs373080197 · VCV178486

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9501 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9501	likely pathogenic
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -8.49	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 7.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.2	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 0.0107% European (non-Finnish) · 126/1,179,454 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00868% 140/1,612,776 alleles · ultra-rare exomes 128/1,460,570 · genomes 12/152,206 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0125%	7,996
European (non-Finnish)grpmax	0.0107%	9,361
Remaining individualsnot grpmax-eligible	0.00961%	10,404

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp1399His
Coding: c.4195G>C
MANE Select: NM_000260
dbSNP: rs373080197
Type: single nucleotide variant
Location: chr11:77194396 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1399: the ferm 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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
MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Gly2187Asp 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-asp1399his (accessed [today's date]).

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