Is ARSH p.Met408Ile (c.1224G>A) pathogenic?

ARSH p.Met408Ile (c.1224G>A) is classified Benign in ARSH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-30). AlphaMissense: ambiguous (0.4824); Common (popmax 8.02%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ARSH p.Met408Ile (c.1224G>A)?

AlphaMissense predicts ambiguous (score 0.4824) — an in-silico prediction, not a clinical call.

ARSH p.Met408Ile

Q: How common is ARSH p.Met408Ile (c.1224G>A) in the general population?

ARSH p.Met408Ile (c.1224G>A) is common (popmax 8.02%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1224G>A · rs61978611 · VCV783900

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4824 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.02%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4824	ambiguous
REVEL	0.253	benign-leaning
SaProt	LLR -5.17	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.37, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	15.44	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 8.02% African / African-American · 4,514/56,316 alleles

Filtering AF 7.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.74%

Overall 0.434% 5,237/1,206,824 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.02%	12
Middle Eastern	0.782%	128
Admixed American	0.692%	144
Remaining individualsnot grpmax-eligible	0.577%	173
South Asian	0.0195%	5,137
European (non-Finnish)	0.0101%	9,937

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: ARSH
Protein: p.Met408Ile
Coding: c.1224G>A
MANE Select: NM_001011719
dbSNP: rs61978611
Type: single nucleotide variant
Location: chrX:3029271 (GRCh38)
Structure: AlphaFold pLDDT 94.15

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

Similar variants

ARSH p.Arg358Cys Benign ★★ same type
ARSH p.Arg37His Benign ★★ ⚠ same type
ARSH p.Pro144Thr Benign ★★ ⚠ same type
ARSH p.Ala100Thr Uncertain significance ★ ⚠ same type
ARSH p.Ala14Thr Uncertain significance ★ ⚠ same type
ARSH p.Ala175Val Uncertain significance ★ ⚠ same type
ARSH p.Ala187Thr Uncertain significance ★ ⚠ same type
ARSH p.Arg106His 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/arsh-p-met408ile (accessed [today's date]).

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