Is ACO2 p.Gly627Ser (c.1879G>A) pathogenic?

ACO2 p.Gly627Ser (c.1879G>A) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.1004); Ultra-rare (popmax 0.05%, amr); Associated with mitochondrial disease.

What condition is associated with ACO2 p.Gly627Ser (c.1879G>A)?

ACO2 p.Gly627Ser (c.1879G>A) is associated with mitochondrial disease (ClinVar).

How common is ACO2 p.Gly627Ser (c.1879G>A) in the general population?

ACO2 p.Gly627Ser (c.1879G>A) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about ACO2 p.Gly627Ser (c.1879G>A)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

ACO2 p.Gly627Ser

c.1879G>A · rs145042292 · VCV1056037

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	24.1	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 0.05% Admixed American · 30/60,014 alleles

Filtering AF 0.0367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0355%

Overall 0.0385% 621/1,613,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.118%	846
Finnishnot grpmax-eligible	0.0765%	1,307
Admixed Americangrpmax	0.05%	2,000
Remaining individualsnot grpmax-eligible	0.0432%	2,313
European (non-Finnish)	0.0397%	2,516
East Asian	0.00891%	11,224
African / African-American	0.00801%	12,488
South Asian	0.0011%	91,066

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly627Ser
Coding: c.1879G>A
MANE Select: NM_001098
dbSNP: rs145042292
Type: single nucleotide variant
Location: chr22:41526379 (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

mitochondrial disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACO2 p.Gly627= Uncertain significance ★ same residue
ACO2 p.Ala500Thr Uncertain significance ★★ ⚠ same condition
ACO2 p.Gly240Ala Uncertain significance ★★ ⚠ same condition
ACO2 p.Asp512Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
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

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-gly627ser (accessed [today's date]).

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