Is ASNS p.Ile375Val (c.1123A>G) pathogenic?

ASNS p.Ile375Val (c.1123A>G) is classified Uncertain significance in ASNS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-09). AlphaMissense: likely benign (0.2239); Ultra-rare (popmax 0.0166%, mid).

How common is ASNS p.Ile375Val (c.1123A>G) in the general population?

ASNS p.Ile375Val (c.1123A>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ASNS p.Ile375Val (c.1123A>G)?

AlphaMissense predicts likely benign (score 0.2239) — an in-silico prediction, not a clinical call.

ASNS p.Ile375Val

c.1123A>G · rs766097318 · VCV1401391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2239 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2239	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -8.20	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 17 kb · p 5.1e-10 · regional, not allelic
Overall
CADD	24.4	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 0.0166% Middle Eastern · 1/6,020 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00267% 43/1,611,258 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,020
European (non-Finnish)	0.0034%	29,454
Remaining individualsnot grpmax-eligible	0.0016%	62,378
African / African-American	0.00134%	74,900

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: ASNS
Protein: p.Ile375Val
Coding: c.1123A>G
MANE Select: NM_001673
dbSNP: rs766097318
Type: single nucleotide variant
Location: chr7:97855367 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 3 PDB
Residue 375: the asparagine synthetase domain; an α-helix

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

Similar variants

ASNS p.Ile375Leu Uncertain significance ★ ⚠ same residue
ASNS c.1030+1G>A Likely pathogenic ★★ same type
ASNS c.1138-1G>A Likely pathogenic ★★ same type
ASNS c.1239-2A>T Likely pathogenic ★★ same type
ASNS c.1320+1G>C Likely pathogenic ★★ same type
ASNS c.1320+1G>T Likely pathogenic ★★ same type
ASNS c.1321-1G>A Likely pathogenic ★★ same type
ASNS c.1476+1G>A Pathogenic ★★ 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/asns-p-ile375val (accessed [today's date]).

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