Is TMEM237 p.Ser297Pro (c.889T>C) pathogenic?

TMEM237 p.Ser297Pro (c.889T>C) is classified Uncertain significance in TMEM237 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-14). AlphaMissense: likely benign (0.0851); Very rare (popmax 0.00017%, nfe); Associated with Joubert syndrome 14.

What condition is associated with TMEM237 p.Ser297Pro (c.889T>C)?

TMEM237 p.Ser297Pro (c.889T>C) is associated with Joubert syndrome 14 (ClinVar).

How common is TMEM237 p.Ser297Pro (c.889T>C) in the general population?

TMEM237 p.Ser297Pro (c.889T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about TMEM237 p.Ser297Pro (c.889T>C)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

TMEM237 p.Ser297Pro

c.889T>C · rs761660963 · VCV2437112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 14

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.79	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 9.2	GERP 2.3, 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

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 0.00017% European (non-Finnish) · 2/1,175,784 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00131% 2/152,098 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.Ser297Pro
Coding: c.889T>C
MANE Select: NM_001044385
dbSNP: rs761660963
Type: single nucleotide variant
Location: chr2:201628130 (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.Ser297Ter Pathogenic ★ same residue
TMEM237 p.Ser297Leu 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-ser297pro (accessed [today's date]).

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