Is MYH3 p.Ile703Met (c.2109C>G) pathogenic?

MYH3 p.Ile703Met (c.2109C>G) is classified Uncertain significance in MYH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-16). AlphaMissense: likely pathogenic (0.9417); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MYH3 p.Ile703Met (c.2109C>G)?

MYH3 p.Ile703Met (c.2109C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MYH3 p.Ile703Met (c.2109C>G) in the general population?

MYH3 p.Ile703Met (c.2109C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MYH3 p.Ile703Met (c.2109C>G)?

AlphaMissense predicts likely pathogenic (score 0.9417) — an in-silico prediction, not a clinical call.

MYH3 p.Ile703Met

c.2109C>G · rs1028328685 · VCV2278571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9417	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -15.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -2.6, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 13 kb · p 1.2e-31 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,613,930 alleles · very rare exomes 1/1,461,632 · genomes 0/152,298 · joint denominator

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.Ile703Met
Coding: c.2109C>G
MANE Select: NM_002470
dbSNP: rs1028328685
Type: single nucleotide variant
Location: chr17:10641141 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.35
Residue 703: the myosin motor domain; a UniProt-annotated variant site (in cpsfs1b)

Full MYH3 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

Similar variants

MYH3 p.Arg1251Ter Pathogenic/Likely pathogenic ★★ same condition
MYH3 p.Ala1131Thr Uncertain significance ★★ ⚠ same condition
MYH3 p.Ala1198Val Uncertain significance ★★ ⚠ same condition
MYH3 p.Ala1331Val Uncertain significance ★★ ⚠ same condition
MYH3 p.Ala1380Val Uncertain significance ★★ ⚠ same condition
MYH3 p.Ala1395Thr Uncertain significance ★★ ⚠ same condition
MYH3 p.Ala13Val Uncertain significance ★★ ⚠ same condition
MYH3 p.Ala1441Thr Uncertain significance ★★ ⚠ 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/myh3-p-ile703met (accessed [today's date]).

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