Is ACO1 p.Pro349Ser (c.1045C>T) pathogenic?

ACO1 p.Pro349Ser (c.1045C>T) is classified Likely benign in ACO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely benign (0.0724); Rare (popmax 0.113%, amr).

How common is ACO1 p.Pro349Ser (c.1045C>T) in the general population?

ACO1 p.Pro349Ser (c.1045C>T) is rare (popmax 0.113%, amr) (gnomAD).

What do computational predictors say about ACO1 p.Pro349Ser (c.1045C>T)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

ACO1 p.Pro349Ser

c.1045C>T · VCV3824143

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -5.09	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 -7.5	GERP -4.8
Regional constraint	o/e 0.87	unconstrained · MANE · 45 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	0.026	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 0.113% Admixed American · 65/57,504 alleles

Filtering AF 0.0909% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0829%

Overall 0.00431% 69/1,600,492 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.113%	885
African / African-American	0.00539%	18,545

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: ACO1
Protein: p.Pro349Ser
Coding: c.1045C>T
MANE Select: NM_002197
Type: single nucleotide variant
Location: chr9:32423393 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 2 PDB
Residue 349: an α-helix

Full ACO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACO1 p.Ala665Val Uncertain significance ★★ ⚠ same type
ACO1 p.Arg885His Uncertain significance ★★ ⚠ same type
ACO1 p.Gly831Arg Uncertain significance ★★ ⚠ same type
ACO1 p.Ala794= Benign ★★ same type
ACO1 p.Asp569= Benign ★★ same type
ACO1 p.His252= Benign ★★ same type
ACO1 p.Pro443= Benign/Likely benign ★★ same type
ACO1 c.474+1G>T 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/aco1-p-pro349ser (accessed [today's date]).

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