Is ASIC2 p.Pro334Ser (c.1000C>T) pathogenic?

ASIC2 p.Pro334Ser (c.1000C>T) is classified Uncertain significance in ASIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.5369); Very rare (popmax 0.00446%, eas).

How common is ASIC2 p.Pro334Ser (c.1000C>T) in the general population?

ASIC2 p.Pro334Ser (c.1000C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ASIC2 p.Pro334Ser (c.1000C>T)?

AlphaMissense predicts ambiguous (score 0.5369) — an in-silico prediction, not a clinical call.

ASIC2 p.Pro334Ser

c.1000C>T · VCV4643474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.5369	ambiguous
REVEL	0.531	indeterminate
SaProt	LLR -8.04	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 75 kb · p 0.00015 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P283S vs ClinVar P334S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,810 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: ASIC2
Protein: p.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_183377
Type: single nucleotide variant
Location: chr17:33028380 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 86.90 · 1 PDB
Residue 334: a disulfide bond

Full ASIC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASIC2 c.988-4G>A Benign ★★ same type
ASIC2 p.Ala293= Benign ★★ same type
ASIC2 p.Ala129Thr Uncertain significance ★ ⚠ same type
ASIC2 p.Ala136Val Uncertain significance ★ ⚠ same type
ASIC2 p.Ala28Glu Uncertain significance ★ same type
ASIC2 p.Ala382Val Uncertain significance ★ ⚠ same type
ASIC2 p.Ala402Val Uncertain significance ★ ⚠ same type
ASIC2 p.Ala47Thr Uncertain significance ★ 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/asic2-p-pro334ser (accessed [today's date]).

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