Is ATOSA p.Ala375Pro (c.1123G>C) pathogenic?

ATOSA p.Ala375Pro (c.1123G>C) is classified Uncertain significance in ATOSA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.8624); Ultra-rare (popmax 0.0957%, sas).

How common is ATOSA p.Ala375Pro (c.1123G>C) in the general population?

ATOSA p.Ala375Pro (c.1123G>C) is ultra-rare (popmax 0.0957%, sas) (gnomAD).

What do computational predictors say about ATOSA p.Ala375Pro (c.1123G>C)?

AlphaMissense predicts likely pathogenic (score 0.8624) — an in-silico prediction, not a clinical call.

ATOSA p.Ala375Pro

c.1123G>C · rs202140626 · VCV3131145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8624 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0957%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8624	likely pathogenic
REVEL	0.353	indeterminate
SaProt	LLR -12.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 17 kb · p 0.027 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0957% South Asian · 87/90,910 alleles

Filtering AF 0.0795% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0734%

Overall 0.049% 790/1,612,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
South Asiangrpmax	0.0957%	1,045
Remaining individualsnot grpmax-eligible	0.0657%	1,522
European (non-Finnish)	0.053%	1,887
Finnishnot grpmax-eligible	0.0422%	2,367
Middle Eastern	0.0165%	6,078
African / African-American	0.00535%	18,702
Admixed American	0.00501%	19,942

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ATOSA
Protein: p.Ala375Pro
Coding: c.1123G>C
MANE Select: NM_001385016
dbSNP: rs202140626
Type: single nucleotide variant
Location: chr15:52609791 (GRCh38)
Structure: AlphaFold pLDDT 55.15

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

Similar variants

ATOSA p.Ala116Val Uncertain significance ★ ⚠ same type
ATOSA p.Ala121Val Uncertain significance ★ ⚠ same type
ATOSA p.Ala294Gly Uncertain significance ★ ⚠ same type
ATOSA p.Arg1012Gln Uncertain significance ★ ⚠ same type
ATOSA p.Arg134Gln Uncertain significance ★ ⚠ same type
ATOSA p.Arg266Cys Uncertain significance ★ ⚠ same type
ATOSA p.Arg266His Uncertain significance ★ ⚠ same type
ATOSA p.Arg349Cys 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/atosa-p-ala375pro (accessed [today's date]).

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