Is ATOSB p.Val421Met (c.1261G>A) pathogenic?

ATOSB p.Val421Met (c.1261G>A) is classified Uncertain significance in ATOSB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-18). AlphaMissense: likely pathogenic (0.7817); Very rare (popmax 0.00329%, sas).

How common is ATOSB p.Val421Met (c.1261G>A) in the general population?

ATOSB p.Val421Met (c.1261G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ATOSB p.Val421Met (c.1261G>A)?

AlphaMissense predicts likely pathogenic (score 0.7817) — an in-silico prediction, not a clinical call.

ATOSB p.Val421Met

c.1261G>A · rs573980235 · VCV2557075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7817	likely pathogenic
REVEL	0.171	moderately benign-leaning
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 1,348 bp · p 7.4e-07 · regional, not allelic
Overall
CADD	25.4	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00142% 23/1,614,082 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
Finnishnot grpmax-eligible	0.00156%	64,032
European (non-Finnish)	0.00153%	65,555
African / African-American	0.00133%	75,016

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: ATOSB
Protein: p.Val421Met
Coding: c.1261G>A
MANE Select: NM_025182
dbSNP: rs573980235
Type: single nucleotide variant
Location: chr9:35105967 (GRCh38)
Structure: AlphaFold pLDDT 56.25
Residue 421: the 'required for macropage invasion' region

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

Similar variants

ATOSB p.Ala161Val Uncertain significance ★ ⚠ same type
ATOSB p.Ala194Thr Uncertain significance ★ ⚠ same type
ATOSB p.Ala220Thr Uncertain significance ★ ⚠ same type
ATOSB p.Ala27Ser Uncertain significance ★ ⚠ same type
ATOSB p.Ala6Val Uncertain significance ★ ⚠ same type
ATOSB p.Arg263Gln Uncertain significance ★ ⚠ same type
ATOSB p.Arg263Trp Uncertain significance ★ ⚠ same type
ATOSB p.Arg265His 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/atosb-p-val421met (accessed [today's date]).

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