Is ASIC2 p.Phe49Ser (c.146T>C) pathogenic?

ASIC2 p.Phe49Ser (c.146T>C) is classified Uncertain significance in ASIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.9412); Absent from gnomAD v4.1.

How common is ASIC2 p.Phe49Ser (c.146T>C) in the general population?

ASIC2 p.Phe49Ser (c.146T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ASIC2 p.Phe49Ser (c.146T>C)?

AlphaMissense predicts likely pathogenic (score 0.9412) — an in-silico prediction, not a clinical call.

ASIC2 p.Phe49Ser

c.146T>C · VCV3952740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9412 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9412	likely pathogenic
REVEL	0.522	indeterminate
SaProt	LLR -13.01	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 11	GERP 1.9, phastCons 1
Overall
CADD	25.6	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

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: ASIC2
Protein: p.Phe49Ser
Coding: c.146T>C
MANE Select: NM_183377 · reported on NM_001094
Type: single nucleotide variant
Location: chr17:34156387 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 86.90 · 1 PDB
Residue 49: an α-helix

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-phe49ser (accessed [today's date]).

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