Is ACO2 p.Asn350Ser (c.1049A>G) pathogenic?

ACO2 p.Asn350Ser (c.1049A>G) is classified Benign/Likely benign in ACO2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-15). AlphaMissense: likely benign (0.2276); Rare (popmax 0.565%, sas).

How common is ACO2 p.Asn350Ser (c.1049A>G) in the general population?

ACO2 p.Asn350Ser (c.1049A>G) is rare (popmax 0.565%, sas) (gnomAD).

What do computational predictors say about ACO2 p.Asn350Ser (c.1049A>G)?

AlphaMissense predicts likely benign (score 0.2276) — an in-silico prediction, not a clinical call.

ACO2 p.Asn350Ser

c.1049A>G · rs370742333 · VCV214020

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2276 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.565%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2276	likely benign
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -11.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	26.2	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 0.565% South Asian · 514/91,052 alleles

Filtering AF 0.524% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.508%

Overall 0.0326% 526/1,613,500 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.565%	177
Remaining individualsnot grpmax-eligible	0.008%	12,493
European (non-Finnish)	0.000593%	168,516

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: ACO2
Protein: p.Asn350Ser
Coding: c.1049A>G
MANE Select: NM_001098
dbSNP: rs370742333
Type: single nucleotide variant
Location: chr22:41520187 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44

Full ACO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Arg84Ter Pathogenic ★★ same type
ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Gly503Ter Pathogenic ★★ same type
ACO2 c.1605+5G>C Uncertain significance ★★ same type
ACO2 c.2208+5G>C Uncertain significance ★★ same type
ACO2 c.2208+5G>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/aco2-p-asn350ser (accessed [today's date]).

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