Is TMEM237 p.Arg192Pro (c.575G>C) pathogenic?

TMEM237 p.Arg192Pro (c.575G>C) is classified Uncertain significance in TMEM237 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.7769); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMEM237 p.Arg192Pro (c.575G>C)?

TMEM237 p.Arg192Pro (c.575G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMEM237 p.Arg192Pro (c.575G>C) in the general population?

TMEM237 p.Arg192Pro (c.575G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TMEM237 p.Arg192Pro (c.575G>C)?

AlphaMissense predicts likely pathogenic (score 0.7769) — an in-silico prediction, not a clinical call.

TMEM237 p.Arg192Pro

c.575G>C · VCV4186763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7769	likely pathogenic · top 9% in TMEM237
REVEL	0.345	indeterminate
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 19 kb · p 0.88 · 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 8.48e-05% European (non-Finnish) · 1/1,179,602 alleles

Overall 6.2e-05% 1/1,612,676 alleles · very rare exomes 1/1,460,460 · genomes 0/152,216 · 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.Arg192Pro
Coding: c.575G>C
MANE Select: NM_001044385
Type: single nucleotide variant
Location: chr2:201629831 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMEM237 p.Arg192Cys Uncertain significance ★★ same residue
TMEM237 p.Arg192His Uncertain significance ★★ ⚠ same residue
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.Asp292Val Uncertain significance ★★ ⚠ same condition
TMEM237 p.Glu77Asp 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-arg192pro (accessed [today's date]).

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