Is ASIC3 p.Arg152Cys (c.454C>T) pathogenic?

ASIC3 p.Arg152Cys (c.454C>T) is classified Uncertain significance in ASIC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: likely pathogenic (0.6517); Ultra-rare (popmax 0.0483%, sas).

How common is ASIC3 p.Arg152Cys (c.454C>T) in the general population?

ASIC3 p.Arg152Cys (c.454C>T) is ultra-rare (popmax 0.0483%, sas) (gnomAD).

What do computational predictors say about ASIC3 p.Arg152Cys (c.454C>T)?

AlphaMissense predicts likely pathogenic (score 0.6517) — an in-silico prediction, not a clinical call.

ASIC3 p.Arg152Cys

c.454C>T · rs777603969 · VCV2217229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6517 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6517	likely pathogenic
REVEL	0.528	indeterminate
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.76, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,763 bp · p 0.2 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0483% South Asian · 44/91,068 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00651% 105/1,612,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0483%	2,070
Middle Eastern	0.0329%	3,042
African / African-American	0.00934%	10,702
Remaining individualsnot grpmax-eligible	0.0064%	15,616
European (non-Finnish)	0.00407%	24,581

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: ASIC3
Protein: p.Arg152Cys
Coding: c.454C>T
MANE Select: NM_004769
dbSNP: rs777603969
Type: single nucleotide variant
Location: chr7:151049339 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.15
Residue 152: a disulfide bond

Full ASIC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASIC3 p.Arg79Ter Uncertain significance ★★ same type
ASIC3 p.Pro289Ser Benign ★★ same type
ASIC3 c.1518-4G>A Uncertain significance ★ same type
ASIC3 c.*27C>T Uncertain significance ★ same type
ASIC3 c.*3C>A Uncertain significance ★ same type
ASIC3 c.*3C>T Uncertain significance ★ same type
ASIC3 p.Ala110Ser Uncertain significance ★ ⚠ same type
ASIC3 p.Ala120Thr 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/asic3-p-arg152cys (accessed [today's date]).

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