Is ACO2 p.Asp538Val (c.1613A>T) pathogenic?

ACO2 p.Asp538Val (c.1613A>T) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-24). AlphaMissense: likely benign (0.2084); Very rare (popmax 0.00668%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACO2 p.Asp538Val (c.1613A>T)?

ACO2 p.Asp538Val (c.1613A>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACO2 p.Asp538Val (c.1613A>T) in the general population?

ACO2 p.Asp538Val (c.1613A>T) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about ACO2 p.Asp538Val (c.1613A>T)?

AlphaMissense predicts likely benign (score 0.2084) — an in-silico prediction, not a clinical call.

ACO2 p.Asp538Val

c.1613A>T · rs1012815978 · VCV2228705

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2084	likely benign
REVEL	0.54	indeterminate
SaProt	LLR -12.94	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	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	24.6	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 0.00668% African / African-American · 5/74,884 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00031% 5/1,613,780 alleles · very rare exomes 2/1,461,692 · genomes 3/152,088 · joint denominator

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.Asp538Val
Coding: c.1613A>T
MANE Select: NM_001098
dbSNP: rs1012815978
Type: single nucleotide variant
Location: chr22:41525200 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44
Residue 538: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACO2 c.1605+5G>C Uncertain significance ★★ same condition
ACO2 c.2208+5G>T Uncertain significance ★★ same condition
ACO2 p.Ala500Thr Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg141His Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg18Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg61Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg633Leu Uncertain significance ★★ ⚠ same condition
ACO2 p.Asp542Ala 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-asp538val (accessed [today's date]).

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