Is COA4 p.Asp19Glu (c.57T>G) pathogenic?

COA4 p.Asp19Glu (c.57T>G) is classified Uncertain significance in COA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-07). AlphaMissense: likely benign (0.0621); Very rare (popmax 0.00167%, amr).

How common is COA4 p.Asp19Glu (c.57T>G) in the general population?

COA4 p.Asp19Glu (c.57T>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about COA4 p.Asp19Glu (c.57T>G)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

COA4 p.Asp19Glu

c.57T>G · VCV3494867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -4.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -2.3
Regional constraint	o/e 0.86	unconstrained · MANE · 260 bp · p 0.15 · regional, not allelic
Overall
CADD	0.729	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 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,614,080 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000339%	295,010

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.Asp19Glu
Coding: c.57T>G
MANE Select: NM_016565
Type: single nucleotide variant
Location: chr11:73873322 (GRCh38)
Gene constraint: LOEUF 1.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37
Residue 19: the 'disordered' region

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

Similar variants

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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-asp19glu (accessed [today's date]).

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