Is MYH3 p.Arg1663Trp (c.4987C>T) pathogenic?

MYH3 p.Arg1663Trp (c.4987C>T) is classified Conflicting classifications of pathogenicity in MYH3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.2051); Very rare (popmax 0.00669%, nfe).

How common is MYH3 p.Arg1663Trp (c.4987C>T) in the general population?

MYH3 p.Arg1663Trp (c.4987C>T) is very rare (popmax 0.00669%, nfe) (gnomAD).

What do computational predictors say about MYH3 p.Arg1663Trp (c.4987C>T)?

AlphaMissense predicts likely benign (score 0.2051) — an in-silico prediction, not a clinical call.

MYH3 p.Arg1663Trp

c.4987C>T · rs777159320 · VCV1188002

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2051 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2051	likely benign
REVEL	0.748	pathogenic-leaning
SaProt	LLR -16.29	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	33.0	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 0.00669% European (non-Finnish) · 79/1,180,058 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00818% 132/1,613,648 alleles · very rare exomes 120/1,461,434 · genomes 12/152,214 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0625%	1,600
Remaining individualsnot grpmax-eligible	0.00801%	12,489
European (non-Finnish)grpmax	0.00669%	14,937
African / African-American	0.004%	24,972
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.00329%	30,355
Admixed American	0.00167%	60,010

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: MYH3
Protein: p.Arg1663Trp
Coding: c.4987C>T
MANE Select: NM_002470
dbSNP: rs777159320
Type: single nucleotide variant
Location: chr17:10631986 (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.Arg1663Gln Uncertain significance ★ ⚠ same residue
MYH3 p.Arg1663Gly Uncertain significance ★ ⚠ 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-arg1663trp (accessed [today's date]).

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