Is ASIC4 p.Val33Ala (c.98T>C) pathogenic?

ASIC4 p.Val33Ala (c.98T>C) is classified Likely benign in ASIC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-21). AlphaMissense: likely benign (0.0469); Rare (popmax 0.707%, afr).

How common is ASIC4 p.Val33Ala (c.98T>C) in the general population?

ASIC4 p.Val33Ala (c.98T>C) is rare (popmax 0.707%, afr) (gnomAD).

What do computational predictors say about ASIC4 p.Val33Ala (c.98T>C)?

AlphaMissense predicts likely benign (score 0.0469) — an in-silico prediction, not a clinical call.

ASIC4 p.Val33Ala

c.98T>C · rs116598338 · VCV782739

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0469 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.707%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0469	likely benign
REVEL	0.114	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.1, phastCons 0.8
Regional constraint	o/e 0.89	unconstrained · MANE · 23 kb · p 0.0028 · regional, not allelic
Overall
CADD	11.8	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 V160A vs ClinVar V33A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.707% African / African-American · 530/75,012 alleles

Filtering AF 0.657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.637%

Overall 0.545% 8,795/1,613,266 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.82%	21
African / African-Americangrpmax	0.707%	142
Finnishnot grpmax-eligible	0.648%	154
European (non-Finnish)	0.606%	165
Remaining individualsnot grpmax-eligible	0.536%	187
Ashkenazi Jewishnot grpmax-eligible	0.301%	333
Admixed American	0.297%	337
Middle Eastern	0.149%	673
South Asian	0.0494%	2,024

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ASIC4
Protein: p.Val33Ala
Coding: c.98T>C
MANE Select: NM_018674
dbSNP: rs116598338
Type: single nucleotide variant
Location: chr2:219514822 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.37

Full ASIC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASIC4 p.Ala127= Benign ★★ same type
ASIC4 p.Ala298Thr Benign ★★ same type
ASIC4 p.Arg475= Benign ★★ same type
ASIC4 p.Pro113= Benign ★★ same type
ASIC4 p.Glu383Lys Uncertain significance ★ same type
ASIC4 p.Pro368= Likely benign ★ same type
ASIC4 p.Thr245= Likely 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/asic4-p-val33ala (accessed [today's date]).

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