Is ACO2 p.Lys258Asn (c.774A>T) pathogenic?

ACO2 p.Lys258Asn (c.774A>T) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-17). AlphaMissense: likely pathogenic (0.8938); Very rare (popmax 0.000339%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with ACO2 p.Lys258Asn (c.774A>T)?

ACO2 p.Lys258Asn (c.774A>T) is associated with inherited retinal dystrophy (ClinVar).

How common is ACO2 p.Lys258Asn (c.774A>T) in the general population?

ACO2 p.Lys258Asn (c.774A>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ACO2 p.Lys258Asn (c.774A>T)?

AlphaMissense predicts likely pathogenic (score 0.8938) — an in-silico prediction, not a clinical call.

ACO2 p.Lys258Asn

c.774A>T · rs751703387 · VCV1497959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.8938	likely pathogenic
REVEL	0.442	indeterminate
SaProt	LLR -13.97	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 3.5	GERP -0.42, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	24.1	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 0.000339% European (non-Finnish) · 4/1,180,046 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,890 alleles · very rare

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.Lys258Asn
Coding: c.774A>T
MANE Select: NM_001098
dbSNP: rs751703387
Type: single nucleotide variant
Location: chr22:41515856 (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

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

Similar variants

ACO2 p.Gly240Ala Uncertain significance ★★ ⚠ same condition
ACO2 p.Thr761Met Uncertain significance ★★ ⚠ same condition
ACO2 p.Val247Ala Uncertain significance ★★ ⚠ same condition
ACO2 p.Gln434Ter Pathogenic ★ same condition
ACO2 p.Leu74Val Conflicting classifications of pathogenicity ★ ⚠ same condition
ACO2 c.1483-5T>G Uncertain significance same condition
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ 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-lys258asn (accessed [today's date]).

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