Is COA3 p.Ala101Pro (c.301G>C) pathogenic?

COA3 p.Ala101Pro (c.301G>C) is classified Uncertain significance in COA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-09). AlphaMissense: ambiguous (0.4007); Ultra-rare (popmax 0.0822%, mid).

How common is COA3 p.Ala101Pro (c.301G>C) in the general population?

COA3 p.Ala101Pro (c.301G>C) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about COA3 p.Ala101Pro (c.301G>C)?

AlphaMissense predicts ambiguous (score 0.4007) — an in-silico prediction, not a clinical call.

COA3 p.Ala101Pro

c.301G>C · VCV3834810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4007 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4007	ambiguous
REVEL	0.136	moderately benign-leaning
SaProt	LLR -13.65	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 2.8, phastCons 0.57
Regional constraint	o/e 1.01	unconstrained · MANE · 617 bp · p 0.91 · regional, not allelic
Overall
CADD	20.8	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 0.0822% Middle Eastern · 5/6,084 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00706% 114/1,613,964 alleles · ultra-rare exomes 108/1,461,794 · genomes 6/152,170 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,217
Remaining individualsnot grpmax-eligible	0.0112%	8,926
European (non-Finnish)	0.0078%	12,826
South Asian	0.00659%	15,179
Admixed American	0.00333%	29,995
African / African-American	0.00267%	37,450

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: COA3
Protein: p.Ala101Pro
Coding: c.301G>C
MANE Select: NM_001040431
Type: single nucleotide variant
Location: chr17:42798081 (GRCh38)
Gene constraint: LOEUF 1.693 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.32

Full COA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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COA3 p.Arg96Gln Uncertain significance ★★ ⚠ same type
COA3 p.Arg96Pro Uncertain significance ★★ ⚠ same type
COA3 p.Arg98Gly Uncertain significance ★★ ⚠ same type
COA3 p.Gly5Arg Uncertain significance ★★ ⚠ same type
COA3 p.Val68Leu Uncertain significance ★★ ⚠ same type
COA3 c.214+6C>T Uncertain significance ★ same type
COA3 p.Ala70Val Uncertain significance ★ ⚠ 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/coa3-p-ala101pro (accessed [today's date]).

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