Is ASIC5 p.Cys22Phe (c.65G>T) pathogenic?

ASIC5 p.Cys22Phe (c.65G>T) is classified Likely benign in ASIC5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely benign (0.0594); Rare (popmax 0.476%, afr); Associated with ASIC5-related disorder.

What condition is associated with ASIC5 p.Cys22Phe (c.65G>T)?

ASIC5 p.Cys22Phe (c.65G>T) is associated with ASIC5-related disorder (ClinVar).

How common is ASIC5 p.Cys22Phe (c.65G>T) in the general population?

ASIC5 p.Cys22Phe (c.65G>T) is rare (popmax 0.476%, afr) (gnomAD).

What do computational predictors say about ASIC5 p.Cys22Phe (c.65G>T)?

AlphaMissense predicts likely benign (score 0.0594) — an in-silico prediction, not a clinical call.

ASIC5 p.Cys22Phe

c.65G>T · rs148021215 · VCV3038790

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0594 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.476%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ASIC5-related disorder

Computational evidence

Protein change
AlphaMissense	0.0594	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.54	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 -0.74	GERP -2.7, phastCons 0.001
Regional constraint	o/e 1.07	unconstrained · MANE · 36 kb · p 0.1 · regional, not allelic
Overall
CADD	12.96	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.476% African / African-American · 357/74,968 alleles

Filtering AF 0.435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.42%

Overall 0.0245% 396/1,613,284 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.476%	210
Remaining individualsnot grpmax-eligible	0.0384%	2,603
Admixed American	0.02%	4,996
European (non-Finnish)	0.000254%	393,255

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: ASIC5
Protein: p.Cys22Phe
Coding: c.65G>T
MANE Select: NM_017419
dbSNP: rs148021215
Type: single nucleotide variant
Location: chr4:155863730 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.59 · 3 PDB
Residue 22: the 'binds the plasma membrane and stabilizes the channel in the closed state' region

Full ASIC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ASIC5-related disorder

Similar variants

ASIC5 p.Ile96Thr Likely benign same condition
ASIC5 p.Ala218Gly Uncertain significance ★ ⚠ same type
ASIC5 p.Ala396Thr Uncertain significance ★ ⚠ same type
ASIC5 p.Ala435Val Uncertain significance ★ ⚠ same type
ASIC5 p.Arg284Cys Uncertain significance ★ ⚠ same type
ASIC5 p.Arg284His Uncertain significance ★ ⚠ same type
ASIC5 p.Arg34Gln Uncertain significance ★ ⚠ same type
ASIC5 p.Arg408Gly 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/asic5-p-cys22phe (accessed [today's date]).

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