Is MYO7A p.Arg1708His (c.5123G>A) pathogenic?

MYO7A p.Arg1708His (c.5123G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.0895); Ultra-rare (popmax 0.0166%, mid); Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Arg1708His (c.5123G>A)?

MYO7A p.Arg1708His (c.5123G>A) is associated with autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg1708His (c.5123G>A) in the general population?

MYO7A p.Arg1708His (c.5123G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about MYO7A p.Arg1708His (c.5123G>A)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1708His

c.5123G>A · rs1241956038 · VCV1028646

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.82	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 0.43, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,016 alleles

Filtering AF 0.00201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00172%

Overall 0.00263% 41/1,558,296 alleles · ultra-rare exomes 39/1,406,312 · genomes 2/151,984 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,016
African / African-American	0.00545%	18,359
European (non-Finnish)	0.00278%	35,963
East Asian	0.00241%	41,566
South Asian	0.00237%	42,223
Admixed American	0.00193%	51,880

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.Arg1708His
Coding: c.5123G>A
MANE Select: NM_000260
dbSNP: rs1241956038
Type: single nucleotide variant
Location: chr11:77202379 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1708: an α-helix

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

Similar variants

MYO7A p.Arg1708Cys Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg1708Leu Uncertain significance ★ ⚠ same residue
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

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-arg1708his (accessed [today's date]).

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