Is ACO2 p.Arg312Trp (c.934C>T) pathogenic?

ACO2 p.Arg312Trp (c.934C>T) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-07-05). AlphaMissense: likely pathogenic (0.9571); Absent from gnomAD v4.1; Associated with isolated macular dystrophy.

What condition is associated with ACO2 p.Arg312Trp (c.934C>T)?

ACO2 p.Arg312Trp (c.934C>T) is associated with isolated macular dystrophy, infantile cerebellar-retinal degeneration, optic atrophy 9 (ClinVar).

How common is ACO2 p.Arg312Trp (c.934C>T) in the general population?

ACO2 p.Arg312Trp (c.934C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACO2 p.Arg312Trp (c.934C>T)?

AlphaMissense predicts likely pathogenic (score 0.9571) — an in-silico prediction, not a clinical call.

ACO2 p.Arg312Trp

c.934C>T · rs2146127377 · VCV1354645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9571 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

isolated macular dystrophy

Computational evidence

Protein change
AlphaMissense	0.9571	likely pathogenic
REVEL	0.439	indeterminate
SaProt	LLR -18.00	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	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	33.0	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

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.Arg312Trp
Coding: c.934C>T
MANE Select: NM_001098
dbSNP: rs2146127377
Type: single nucleotide variant
Location: chr22:41517625 (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

Disease context

isolated macular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: infantile cerebellar-retinal degeneration optic atrophy 9

Similar variants

ACO2 p.Arg312Gln Uncertain significance ★★ ⚠ same residue
ACO2 p.Arg312= Likely benign ★ same residue
ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Gly503Ter Pathogenic ★★ same condition
ACO2 p.Ala647Gly Uncertain significance ★★ ⚠ same condition
ACO2 p.Ala768Thr Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg648Cys Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same condition

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-arg312trp (accessed [today's date]).

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