Is COA4 p.Leu76Pro (c.227T>C) pathogenic?

COA4 p.Leu76Pro (c.227T>C) is classified Uncertain significance in COA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: ambiguous (0.4257); Very rare (popmax 0.0089%, nfe).

How common is COA4 p.Leu76Pro (c.227T>C) in the general population?

COA4 p.Leu76Pro (c.227T>C) is very rare (popmax 0.0089%, nfe) (gnomAD).

What do computational predictors say about COA4 p.Leu76Pro (c.227T>C)?

AlphaMissense predicts ambiguous (score 0.4257) — an in-silico prediction, not a clinical call.

COA4 p.Leu76Pro

c.227T>C · VCV4655292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4257 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0089%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4257	ambiguous
REVEL	0.189	benign-leaning
SaProt	LLR -13.40	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 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 260 bp · p 0.15 · regional, not allelic
Overall
CADD	25.4	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 0.0089% European (non-Finnish) · 105/1,179,346 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00701%

Overall 0.00732% 107/1,460,890 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0089%	11,232
Remaining individualsnot grpmax-eligible	0.0032%	31,239

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.Leu76Pro
Coding: c.227T>C
MANE Select: NM_016565
Type: single nucleotide variant
Location: chr11:73873152 (GRCh38)
Gene constraint: LOEUF 1.74 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37
Residue 76: the 'disordered' region

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

Similar variants

COA4 p.Ala70Val Uncertain significance ★ ⚠ same type
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.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-leu76pro (accessed [today's date]).

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