Is TMEM63A p.Arg296Pro (c.887G>C) pathogenic?

TMEM63A p.Arg296Pro (c.887G>C) is classified Uncertain significance in TMEM63A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.1374); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMEM63A p.Arg296Pro (c.887G>C)?

TMEM63A p.Arg296Pro (c.887G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMEM63A p.Arg296Pro (c.887G>C) in the general population?

TMEM63A p.Arg296Pro (c.887G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TMEM63A p.Arg296Pro (c.887G>C)?

AlphaMissense predicts likely benign (score 0.1374) — an in-silico prediction, not a clinical call.

TMEM63A p.Arg296Pro

c.887G>C · VCV3970766

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1374 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1374	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -8.85	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 -1.7	GERP -3.8
Regional constraint	o/e 0.84	unconstrained · MANE · 22 kb · p 8.4e-05 · regional, not allelic
Overall
CADD	5.345	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 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000434% 7/1,613,972 alleles · very rare exomes 6/1,461,824 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,004
African / African-American	0.00267%	37,458
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.000169%	590,002

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: TMEM63A
Protein: p.Arg296Pro
Coding: c.887G>C
MANE Select: NM_014698
Type: single nucleotide variant
Location: chr1:225862519 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70 · 6 PDB
Residue 296: the 'intracellular linker il2; confers mechanosensitivity' region; a UniProt-annotated variant site (in hld19; uncertain significance)

Full TMEM63A 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

TMEM63A p.Arg296Gln Uncertain significance ★ ⚠ same residue
TMEM63A p.Lys658Arg Uncertain significance ★★ ⚠ same condition
TMEM63A p.Val653Ile Uncertain significance ★★ ⚠ same condition
TMEM63A p.Arg574Gln Likely benign ★★ same condition
TMEM63A p.Met502Thr Likely benign ★★ same condition
TMEM63A p.Ala251Val Uncertain significance ★ ⚠ same condition
TMEM63A p.Ala369Thr Uncertain significance ★ ⚠ same condition
TMEM63A p.Ala457Val 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/tmem63a-p-arg296pro (accessed [today's date]).

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