Is TMEM63A p.Pro175Ser (c.523C>T) pathogenic?

TMEM63A p.Pro175Ser (c.523C>T) is classified Uncertain significance in TMEM63A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely benign (0.172); Absent from gnomAD v4.1.

How common is TMEM63A p.Pro175Ser (c.523C>T) in the general population?

TMEM63A p.Pro175Ser (c.523C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMEM63A p.Pro175Ser (c.523C>T)?

AlphaMissense predicts likely benign (score 0.172) — an in-silico prediction, not a clinical call.

TMEM63A p.Pro175Ser

c.523C>T · VCV4681930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.172 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.172	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP 0.84, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 22 kb · p 8.4e-05 · regional, not allelic
Overall
CADD	21.7	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

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: TMEM63A
Protein: p.Pro175Ser
Coding: c.523C>T
MANE Select: NM_014698
Type: single nucleotide variant
Location: chr1:225867155 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70 · 6 PDB
Residue 175: a UniProt-annotated variant site (in hld19; uncertain significance); a β-strand

Full TMEM63A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMEM63A p.Pro175Leu Uncertain significance ★ ⚠ same residue
TMEM63A p.Gly168Glu Pathogenic ★★ same type
TMEM63A p.Gly567Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
TMEM63A c.952-9T>G Uncertain significance ★★ same type
TMEM63A p.Lys658Arg Uncertain significance ★★ ⚠ same type
TMEM63A p.Val653Ile Uncertain significance ★★ ⚠ same type
EPHX1 p.Asn357= Benign ★★ same type
TMEM63A c.1378-49C>T Benign ★★ same type

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/tmem63a-p-pro175ser (accessed [today's date]).

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