Is TMEM237 p.Ser372Pro (c.1114T>C) pathogenic?

TMEM237 p.Ser372Pro (c.1114T>C) is classified Uncertain significance in TMEM237 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely pathogenic (0.6813); Very rare (popmax 0.000766%, nfe); Associated with Joubert syndrome 14.

What condition is associated with TMEM237 p.Ser372Pro (c.1114T>C)?

TMEM237 p.Ser372Pro (c.1114T>C) is associated with Joubert syndrome 14 (ClinVar).

How common is TMEM237 p.Ser372Pro (c.1114T>C) in the general population?

TMEM237 p.Ser372Pro (c.1114T>C) is very rare (popmax 0.000766%, nfe) (gnomAD).

What do computational predictors say about TMEM237 p.Ser372Pro (c.1114T>C)?

AlphaMissense predicts likely pathogenic (score 0.6813) — an in-silico prediction, not a clinical call.

TMEM237 p.Ser372Pro

c.1114T>C · rs370795793 · VCV2050269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000766%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 14

Computational evidence

Protein change
AlphaMissense	0.6813	likely pathogenic
REVEL	0.191	benign-leaning
SaProt	LLR -10.54	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 19 kb · p 0.88 · regional, not allelic
Overall
CADD	24.3	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 0.000766% European (non-Finnish) · 9/1,175,314 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000561% 9/1,604,946 alleles · very rare

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.Ser372Pro
Coding: c.1114T>C
MANE Select: NM_001044385
dbSNP: rs370795793
Type: single nucleotide variant
Location: chr2:201626071 (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.Ser372Cys 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
TMEM237 p.Arg18Ter 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-ser372pro (accessed [today's date]).

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