Is COA4 p.Ala70Val (c.209C>T) pathogenic?

COA4 p.Ala70Val (c.209C>T) is classified Uncertain significance in COA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely benign (0.0855); Ultra-rare (popmax 0.0533%, afr).

How common is COA4 p.Ala70Val (c.209C>T) in the general population?

COA4 p.Ala70Val (c.209C>T) is ultra-rare (popmax 0.0533%, afr) (gnomAD).

What do computational predictors say about COA4 p.Ala70Val (c.209C>T)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

COA4 p.Ala70Val

c.209C>T · rs143220644 · VCV3146992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.81	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.1	GERP -0.8, phastCons 0.95
Regional constraint	o/e 0.86	unconstrained · MANE · 260 bp · p 0.15 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0533% African / African-American · 40/75,022 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.00403% 65/1,613,908 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0533%	1,876
Middle Eastern	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.008%	12,499
Admixed American	0.00167%	60,006
European (non-Finnish)	0.00136%	73,743
South Asian	0.0011%	91,070

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: COA4
Protein: p.Ala70Val
Coding: c.209C>T
MANE Select: NM_016565
dbSNP: rs143220644
Type: single nucleotide variant
Location: chr11:73873170 (GRCh38)
Gene constraint: LOEUF 1.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37
Residue 70: the chch domain; the 'disordered' region

Full COA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COA4 p.Arg31His Uncertain significance ★ ⚠ same type
COA4 p.Arg52Gln Uncertain significance ★ ⚠ same type
COA4 p.Asp19Glu Uncertain significance ★ ⚠ same type
COA4 p.Gln7Arg Uncertain significance ★ ⚠ same type
COA4 p.Glu20Lys Uncertain significance ★ ⚠ same type
COA4 p.Leu76Pro Uncertain significance ★ ⚠ same type
COA4 p.Ser30Phe Uncertain significance ★ ⚠ same type
COA4 p.Ser4Leu 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/coa4-p-ala70val (accessed [today's date]).

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