Is ACO2 p.Phe414Val (c.1240T>G) pathogenic?

ACO2 p.Phe414Val (c.1240T>G) is classified Pathogenic in ACO2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-10-19). AlphaMissense: likely pathogenic (0.805); Absent from gnomAD v4.1; Associated with infantile cerebellar-retinal degeneration.

What condition is associated with ACO2 p.Phe414Val (c.1240T>G)?

ACO2 p.Phe414Val (c.1240T>G) is associated with infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Phe414Val (c.1240T>G) in the general population?

ACO2 p.Phe414Val (c.1240T>G) is absent from gnomAD v4.1 (gnomAD).

How is Infantile cerebellar-retinal degeneration inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACO2 p.Phe414Val (c.1240T>G)?

AlphaMissense predicts likely pathogenic (score 0.805) — an in-silico prediction, not a clinical call.

ACO2 p.Phe414Val

c.1240T>G · rs2066538446 · VCV978053

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.805 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile cerebellar-retinal degeneration

Computational evidence

Protein change
AlphaMissense	0.805	likely pathogenic ✓ concordant with ClinVar
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -14.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	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	31.0	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.Phe414Val
Coding: c.1240T>G
MANE Select: NM_001098
dbSNP: rs2066538446
Type: single nucleotide variant
Location: chr22:41522931 (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

infantile cerebellar-retinal degeneration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile cerebellar-retinal degeneration (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACO2 p.Glu464Ter Pathogenic/Likely 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
ACO2 p.Arg684Trp Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg90Trp Uncertain significance ★★ ⚠ same condition
ACO2 p.Asn197Ser 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-phe414val (accessed [today's date]).

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