Is ATOSB p.Pro333Ser (c.997C>T) pathogenic?

ATOSB p.Pro333Ser (c.997C>T) is classified Uncertain significance in ATOSB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely benign (0.0643); Ultra-rare (popmax 0.0222%, sas).

How common is ATOSB p.Pro333Ser (c.997C>T) in the general population?

ATOSB p.Pro333Ser (c.997C>T) is ultra-rare (popmax 0.0222%, sas) (gnomAD).

What do computational predictors say about ATOSB p.Pro333Ser (c.997C>T)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

ATOSB p.Pro333Ser

c.997C>T · VCV3803609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -6.09	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 0.39	GERP -1.6, phastCons 0.97
Regional constraint	o/e 1.00	unconstrained · MANE · 1,701 bp · p 0.96 · regional, not allelic
Overall
CADD	8.527	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 0.0222% South Asian · 19/85,416 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00422% 66/1,563,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0222%	4,496
Middle Eastern	0.0166%	6,018
Remaining individualsnot grpmax-eligible	0.00988%	10,119
African / African-American	0.00406%	24,630
European (non-Finnish)	0.00312%	32,037
Admixed American	0.00193%	51,876

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.Pro333Ser
Coding: c.997C>T
MANE Select: NM_025182
Type: single nucleotide variant
Location: chr9:35106600 (GRCh38)
Structure: AlphaFold pLDDT 56.25

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

Similar variants

ATOSB p.Pro333Ala Uncertain significance ★ ⚠ same residue
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

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-pro333ser (accessed [today's date]).

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