Is TMEM237 p.Val80Ala (c.239T>C) pathogenic?

TMEM237 p.Val80Ala (c.239T>C) is classified Uncertain significance in TMEM237 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely benign (0.0824); Very rare (popmax 0.00402%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMEM237 p.Val80Ala (c.239T>C)?

TMEM237 p.Val80Ala (c.239T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMEM237 p.Val80Ala (c.239T>C) in the general population?

TMEM237 p.Val80Ala (c.239T>C) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about TMEM237 p.Val80Ala (c.239T>C)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

TMEM237 p.Val80Ala

c.239T>C · rs1325980885 · VCV3179236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -5.3
Regional constraint	o/e 0.99	unconstrained · MANE · 19 kb · p 0.88 · regional, not allelic
Overall
CADD	6.996	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00402% African / African-American · 3/74,608 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000189% 3/1,585,988 alleles · very rare exomes 2/1,433,800 · genomes 1/152,188 · 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: TMEM237
Protein: p.Val80Ala
Coding: c.239T>C
MANE Select: NM_001044385
dbSNP: rs1325980885
Type: single nucleotide variant
Location: chr2:201636783 (GRCh38)
Gene constraint: LOEUF 1.318 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.79
Residue 80: the 'disordered' region

Full TMEM237 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

TMEM237 c.1038-6T>G Uncertain significance ★★ same condition
TMEM237 p.Arg128Trp Uncertain significance ★★ ⚠ same condition
TMEM237 p.Arg15Cys Uncertain significance ★★ ⚠ same condition
TMEM237 p.Arg15His Uncertain significance ★★ ⚠ same condition
TMEM237 p.Arg192Cys Uncertain significance ★★ same condition
TMEM237 p.Asp292Val Uncertain significance ★★ ⚠ same condition
TMEM237 p.Glu77Asp Uncertain significance ★★ ⚠ same condition
TMEM237 p.Leu219Pro 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/tmem237-p-val80ala (accessed [today's date]).

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