Is MYH3 p.Arg1663Gln (c.4988G>A) pathogenic?

MYH3 p.Arg1663Gln (c.4988G>A) is classified Uncertain significance in MYH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-14). AlphaMissense: likely benign (0.1057); Very rare (popmax 0.00333%, amr).

How common is MYH3 p.Arg1663Gln (c.4988G>A) in the general population?

MYH3 p.Arg1663Gln (c.4988G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MYH3 p.Arg1663Gln (c.4988G>A)?

AlphaMissense predicts likely benign (score 0.1057) — an in-silico prediction, not a clinical call.

MYH3 p.Arg1663Gln

c.4988G>A · rs770789998 · VCV2757312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1057	likely benign
REVEL	0.634	indeterminate
SaProt	LLR -12.79	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 2.6, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	24.9	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 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,608 alleles · very rare exomes 4/1,461,424 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
African / African-American	0.00267%	37,451
European (non-Finnish)	8.47e-05%	1,180,052

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: MYH3
Protein: p.Arg1663Gln
Coding: c.4988G>A
MANE Select: NM_002470
dbSNP: rs770789998
Type: single nucleotide variant
Location: chr17:10631985 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.35
Residue 1663: a UniProt-annotated variant site (in cpsfs1b)

Full MYH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MYH3 p.Arg1663Gly Uncertain significance ★ ⚠ same residue
MYH3 p.Arg1663Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
MYH3 p.Arg1663= Likely benign ★ same residue
MYH3 c.1581+1G>A Pathogenic/Likely pathogenic ★★ same type
MYH3 c.2682+1G>A Likely pathogenic ★★ same type
MYH3 c.533+1G>A Likely pathogenic ★★ same type
MYH3 c.5563-1G>C Likely pathogenic ★★ same type
MYH3 c.-9+1G>A Pathogenic/Likely pathogenic ★★ same type

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/myh3-p-arg1663gln (accessed [today's date]).

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