Is TMEM140 p.Ala153Pro (c.457G>C) pathogenic?

TMEM140 p.Ala153Pro (c.457G>C) is classified Uncertain significance in TMEM140 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). AlphaMissense: ambiguous (0.4487); Absent from gnomAD v4.1.

How common is TMEM140 p.Ala153Pro (c.457G>C) in the general population?

TMEM140 p.Ala153Pro (c.457G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMEM140 p.Ala153Pro (c.457G>C)?

AlphaMissense predicts ambiguous (score 0.4487) — an in-silico prediction, not a clinical call.

TMEM140 p.Ala153Pro

c.457G>C · VCV3457813

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4487 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4487	ambiguous
REVEL	0.192	benign-leaning
SaProt	LLR -14.52	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 554 bp · p 0.62 · regional, not allelic
Overall
CADD	22.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMEM140
Protein: p.Ala153Pro
Coding: c.457G>C
MANE Select: NM_024033 · reported on NM_018295
Type: single nucleotide variant
Location: chr7:135164898 (GRCh38)

Full TMEM140 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/tmem140-p-ala153pro (accessed [today's date]).

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