Is TMEM237 p.Val249Ile (c.745G>A) pathogenic?

TMEM237 p.Val249Ile (c.745G>A) is classified Uncertain significance in TMEM237 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-04). AlphaMissense: likely benign (0.0819); Very rare (popmax 6.21e-05%); Associated with Joubert syndrome 14.

What condition is associated with TMEM237 p.Val249Ile (c.745G>A)?

TMEM237 p.Val249Ile (c.745G>A) is associated with Joubert syndrome 14 (ClinVar).

How common is TMEM237 p.Val249Ile (c.745G>A) in the general population?

TMEM237 p.Val249Ile (c.745G>A) is very rare (popmax 6.21e-05%) (gnomAD).

What do computational predictors say about TMEM237 p.Val249Ile (c.745G>A)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

TMEM237 p.Val249Ile

c.745G>A · VCV3585233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.21e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 14

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.006	GERP -0.072
Regional constraint	o/e 0.99	unconstrained · MANE · 19 kb · p 0.88 · regional, not allelic
Overall
CADD	13.21	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 6.21e-05%

Overall 6.21e-05% 1/1,610,000 alleles · very rare exomes 1/1,457,706 · genomes 0/152,294 · 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.Val249Ile
Coding: c.745G>A
MANE Select: NM_001044385
Type: single nucleotide variant
Location: chr2:201629354 (GRCh38)
Gene constraint: LOEUF 1.318 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.79

Full TMEM237 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMEM237 p.Val249= Likely benign ★ same residue
TMEM237 p.Val249Leu Uncertain significance ★ ⚠ same residue
TMEM237 c.136+1G>T Likely pathogenic ★★ same condition
TMEM237 c.553+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM237 c.677+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM237 c.869+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM237 c.943+1G>T Pathogenic ★★ same condition
TMEM237 p.Arg109Ter Pathogenic ★★ 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-val249ile (accessed [today's date]).

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