Is MYO7A p.Arg1708Cys (c.5122C>T) pathogenic?

MYO7A p.Arg1708Cys (c.5122C>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1257); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with MYO7A p.Arg1708Cys (c.5122C>T)?

MYO7A p.Arg1708Cys (c.5122C>T) is associated with Inborn genetic diseases, Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Arg1708Cys (c.5122C>T) in the general population?

MYO7A p.Arg1708Cys (c.5122C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about MYO7A p.Arg1708Cys (c.5122C>T)?

AlphaMissense predicts likely benign (score 0.1257) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1708Cys

c.5122C>T · rs529974676 · VCV836928

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1257 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1257	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	25.5	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 0.0167% Middle Eastern · 1/5,992 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000825%

Overall 0.000834% 13/1,558,270 alleles · ultra-rare exomes 8/1,406,252 · genomes 5/152,018 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,992
Admixed American	0.00578%	17,302
South Asian	0.00355%	28,145
Remaining individualsnot grpmax-eligible	0.00166%	60,412
European (non-Finnish)	0.000435%	230,149

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.Arg1708Cys
Coding: c.5122C>T
MANE Select: NM_000260
dbSNP: rs529974676
Type: single nucleotide variant
Location: chr11:77202378 (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

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

Also linked: Usher syndrome type 1B

Similar variants

MYO7A p.Arg1708Leu Uncertain significance ★ ⚠ same residue
MYO7A p.Arg1708His 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
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-arg1708cys (accessed [today's date]).

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