Is IDO1 p.Pro28Ser (c.82C>T) pathogenic?

IDO1 p.Pro28Ser (c.82C>T) is classified Uncertain significance in IDO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.5975); Ultra-rare (popmax 0.0122%, afr).

How common is IDO1 p.Pro28Ser (c.82C>T) in the general population?

IDO1 p.Pro28Ser (c.82C>T) is ultra-rare (popmax 0.0122%, afr) (gnomAD).

What do computational predictors say about IDO1 p.Pro28Ser (c.82C>T)?

AlphaMissense predicts likely pathogenic (score 0.5975) — an in-silico prediction, not a clinical call.

IDO1 p.Pro28Ser

c.82C>T · VCV4273459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5975 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5975	likely pathogenic
REVEL	0.528	indeterminate
SaProt	LLR -10.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 14 kb · p 0.28 · regional, not allelic
Overall
CADD	24.5	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 0.0122% African / African-American · 9/73,710 alleles

Filtering AF 0.00633% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.000703% 11/1,564,346 alleles · ultra-rare exomes 4/1,412,158 · genomes 7/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0122%	8,190
Remaining individualsnot grpmax-eligible	0.00164%	60,812
European (non-Finnish)	8.67e-05%	1,153,277

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: IDO1
Protein: p.Pro28Ser
Coding: c.82C>T
MANE Select: NM_002164
Type: single nucleotide variant
Location: chr8:39914004 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.40 · 85 PDB

Full IDO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IDO1 c.708-3T>C Likely benign ★★ same type
IDO1 p.Ala4Thr Benign ★★ same type
IDO1 p.Glu318= Benign ★★ same type
IDO1 p.Pro142Leu Benign ★★ ⚠ same type
IDO1 p.Ala199Pro Uncertain significance ★ ⚠ same type
IDO1 p.Ala204Ser Uncertain significance ★ ⚠ same type
IDO1 p.Ala326Gly Uncertain significance ★ ⚠ same type
IDO1 p.Ala334Thr 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/ido1-p-pro28ser (accessed [today's date]).

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