Is ARSG p.Leu425Arg (c.1274T>G) pathogenic?

ARSG p.Leu425Arg (c.1274T>G) is classified Uncertain significance in ARSG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-19). AlphaMissense: likely benign (0.1389); Very rare (popmax 0.00133%, afr).

How common is ARSG p.Leu425Arg (c.1274T>G) in the general population?

ARSG p.Leu425Arg (c.1274T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ARSG p.Leu425Arg (c.1274T>G)?

AlphaMissense predicts likely benign (score 0.1389) — an in-silico prediction, not a clinical call.

ARSG p.Leu425Arg

c.1274T>G · rs140303640 · VCV1472951

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1389	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -8.87	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 4	GERP 0.65, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 113 kb · p 0.075 · regional, not allelic
Overall
CADD	24.6	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 0.00133% African / African-American · 1/74,938 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,950 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,938
European (non-Finnish)	0.000932%	107,264

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: ARSG
Protein: p.Leu425Arg
Coding: c.1274T>G
MANE Select: NM_001267727
dbSNP: rs140303640
Type: single nucleotide variant
Location: chr17:68401421 (GRCh38)
Gene constraint: LOEUF 0.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90

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

Similar variants

ARSG p.Leu425= Likely benign ★ same residue
ARSG c.1091+1G>A Likely pathogenic ★★ same type
ARSG c.982+2T>G Likely pathogenic ★★ same type
ARSG p.Ala180Val Uncertain significance ★★ ⚠ same type
ARSG p.Ala262Val Uncertain significance ★★ ⚠ same type
ARSG p.Ala313Val Uncertain significance ★★ ⚠ same type
ARSG p.Ala374Pro Uncertain significance ★★ ⚠ same type
ARSG p.Ala437Val 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/arsg-p-leu425arg (accessed [today's date]).

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