Is ACO2 p.Ser295Phe (c.884C>T) pathogenic?

ACO2 p.Ser295Phe (c.884C>T) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: likely pathogenic (0.9983); Absent from gnomAD v4.1.

How common is ACO2 p.Ser295Phe (c.884C>T) in the general population?

ACO2 p.Ser295Phe (c.884C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACO2 p.Ser295Phe (c.884C>T)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

ACO2 p.Ser295Phe

c.884C>T · rs2146127317 · VCV1483111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9983 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9983	likely pathogenic · top 5% in ACO2
REVEL	0.539	indeterminate
SaProt	LLR -16.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.56 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACO2
Protein: p.Ser295Phe
Coding: c.884C>T
MANE Select: NM_001098
dbSNP: rs2146127317
Type: single nucleotide variant
Location: chr22:41517575 (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.Ser295= Likely benign ★★ same residue
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

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-ser295phe (accessed [today's date]).

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