Is MYO7A p.Arg1420His (c.4259G>A) pathogenic?

MYO7A p.Arg1420His (c.4259G>A) is classified Uncertain significance in MYO7A (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-18). AlphaMissense: ambiguous (0.3593); Very rare (popmax 0.00667%, sas); Associated with Usher syndrome type 1B.

What condition is associated with MYO7A p.Arg1420His (c.4259G>A)?

MYO7A p.Arg1420His (c.4259G>A) is associated with Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Arg1420His (c.4259G>A) in the general population?

MYO7A p.Arg1420His (c.4259G>A) is very rare (popmax 0.00667%, sas) (gnomAD).

What do computational predictors say about MYO7A p.Arg1420His (c.4259G>A)?

AlphaMissense predicts ambiguous (score 0.3593) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1420His

c.4259G>A · rs568337942 · VCV956469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3593 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, sas)

Conditions

Usher syndrome type 1B

Computational evidence

Protein change
AlphaMissense	0.3593	ambiguous
REVEL	0.635	indeterminate
SaProt	LLR -6.83	tolerated
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 0.00667% South Asian · 6/89,906 alleles

Filtering AF 0.00289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00197%

Overall 0.00217% 35/1,609,920 alleles · very rare exomes 32/1,457,624 · genomes 3/152,296 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00667%	14,984
African / African-American	0.004%	24,977
Admixed American	0.00336%	29,748
Remaining individualsnot grpmax-eligible	0.00321%	31,169
European (non-Finnish)	0.00187%	53,558

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.Arg1420His
Coding: c.4259G>A
MANE Select: NM_000260
dbSNP: rs568337942
Type: single nucleotide variant
Location: chr11:77194460 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1420: the ferm 1 domain

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

Disease context

Usher syndrome type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Arg1420Cys Uncertain significance ★ ⚠ same residue
MYO7A p.Arg1420= 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-arg1420his (accessed [today's date]).

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