Is ASIC5 p.Ile253Phe (c.757A>T) pathogenic?

ASIC5 p.Ile253Phe (c.757A>T) is classified Uncertain significance in ASIC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.196); Very rare (popmax 0.00446%, eas).

How common is ASIC5 p.Ile253Phe (c.757A>T) in the general population?

ASIC5 p.Ile253Phe (c.757A>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ASIC5 p.Ile253Phe (c.757A>T)?

AlphaMissense predicts likely benign (score 0.196) — an in-silico prediction, not a clinical call.

ASIC5 p.Ile253Phe

c.757A>T · rs554773690 · VCV3130383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.196	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -7.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 1.2	GERP -0.38, phastCons 0.91
Regional constraint	o/e 1.07	unconstrained · MANE · 36 kb · p 0.1 · regional, not allelic
Overall
CADD	16.35	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00446% East Asian · 2/44,842 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,613,612 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: ASIC5
Protein: p.Ile253Phe
Coding: c.757A>T
MANE Select: NM_017419
dbSNP: rs554773690
Type: single nucleotide variant
Location: chr4:155843785 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.59 · 3 PDB

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

Similar variants

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
ASIC5 p.Arg408Trp 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-ile253phe (accessed [today's date]).

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