Is ARG1 p.Val249Ala (c.746T>C) pathogenic?

ARG1 p.Val249Ala (c.746T>C) is classified Uncertain significance in ARG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-15). AlphaMissense: likely benign (0.0945); Ultra-rare (popmax 0.0187%, afr); Associated with arginase deficiency.

What condition is associated with ARG1 p.Val249Ala (c.746T>C)?

ARG1 p.Val249Ala (c.746T>C) is associated with arginase deficiency (ClinVar).

How common is ARG1 p.Val249Ala (c.746T>C) in the general population?

ARG1 p.Val249Ala (c.746T>C) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

How is Argininemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ARG1 p.Val249Ala (c.746T>C)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

ARG1 p.Val249Ala

c.746T>C · rs755779260 · VCV958983

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arginase deficiency

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -6.46	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 0.5	GERP -3.5
Overall
CADD	6.092	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 0.0187% African / African-American · 14/74,924 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.000929% 15/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,352
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: ARG1
Protein: p.Val249Ala
Coding: c.746T>C
MANE Select: NM_000045
dbSNP: rs755779260
Type: single nucleotide variant
Location: chr6:131583435 (GRCh38)
Gene constraint: LOEUF 0.833 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.01 · 60 PDB

Full ARG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arginase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Argininemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Finland)

Similar variants

ARG1 p.Val249Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ARG1 p.Val249Met Uncertain significance ★ ⚠ same residue
ARG1 c.130+1G>A Pathogenic ★★ same condition
ARG1 c.465+1G>A Likely pathogenic ★★ same condition
ARG1 c.466-1G>C Pathogenic ★★ same condition
ARG1 c.466-2A>G Pathogenic/Likely pathogenic ★★ same condition
ARG1 c.560+2T>C Pathogenic ★★ same condition
ARG1 c.57+1G>A Pathogenic/Likely pathogenic ★★ same condition

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/arg1-p-val249ala (accessed [today's date]).

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