Is MYH2 p.Leu1237Phe (c.3709C>T) pathogenic?

MYH2 p.Leu1237Phe (c.3709C>T) is classified Uncertain significance in MYH2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.1932); Ultra-rare (popmax 0.013%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MYH2 p.Leu1237Phe (c.3709C>T)?

MYH2 p.Leu1237Phe (c.3709C>T) is associated with Inborn genetic diseases, myopathy, proximal, and ophthalmoplegia (ClinVar).

How common is MYH2 p.Leu1237Phe (c.3709C>T) in the general population?

MYH2 p.Leu1237Phe (c.3709C>T) is ultra-rare (popmax 0.013%, nfe) (gnomAD).

What do computational predictors say about MYH2 p.Leu1237Phe (c.3709C>T)?

AlphaMissense predicts likely benign (score 0.1932) — an in-silico prediction, not a clinical call.

MYH2 p.Leu1237Phe

c.3709C>T · rs138265883 · VCV321672

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.013%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1932	likely benign
REVEL	0.61	indeterminate
SaProt	LLR -12.77	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.9	GERP 0.96, phastCons 0.98
Regional constraint	o/e 0.87	unconstrained · MANE · 4,760 bp · p 0.00051 · regional, not allelic
Overall
CADD	26.7	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 0.013% European (non-Finnish) · 153/1,180,010 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00967% 156/1,613,990 alleles · ultra-rare exomes 148/1,461,814 · genomes 8/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.013%	7,712
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,472
South Asian	0.0011%	91,078

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: MYH2
Protein: p.Leu1237Phe
Coding: c.3709C>T
MANE Select: NM_017534
dbSNP: rs138265883
Type: single nucleotide variant
Location: chr17:10528725 (GRCh38)

Full MYH2 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: myopathy, proximal, and ophthalmoplegia

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/myh2-p-leu1237phe (accessed [today's date]).

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