Is COA8 p.Pro73His (c.218C>A) pathogenic?

COA8 p.Pro73His (c.218C>A) is classified Uncertain significance in COA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: ambiguous (0.4337); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with COA8 p.Pro73His (c.218C>A)?

COA8 p.Pro73His (c.218C>A) is associated with Inborn genetic diseases (ClinVar).

How common is COA8 p.Pro73His (c.218C>A) in the general population?

COA8 p.Pro73His (c.218C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COA8 p.Pro73His (c.218C>A)?

AlphaMissense predicts ambiguous (score 0.4337) — an in-silico prediction, not a clinical call.

COA8 p.Pro73His

c.218C>A · VCV4004757

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4337 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4337	ambiguous
REVEL	0.289	benign-leaning
SaProt	LLR -13.35	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 5.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 27 kb · p 0.018 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P86H vs ClinVar P73H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COA8
Protein: p.Pro73His
Coding: c.218C>A
MANE Select: NM_001370595
Type: single nucleotide variant
Location: chr14:103571717 (GRCh38)
Gene constraint: LOEUF 1.305 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.19

Full COA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COA8 p.Pro73Ala Uncertain significance ★ ⚠ same residue
COA8 c.-32C>G Uncertain significance ★★ ⚠ same condition
COA8 p.Ala140Val Uncertain significance ★★ ⚠ same condition
COA8 p.Ala27Val Uncertain significance ★★ ⚠ same condition
COA8 p.Arg164Cys Uncertain significance ★★ ⚠ same condition
COA8 p.Asn135Ser Uncertain significance ★★ ⚠ same condition
COA8 p.Asn165Ser Uncertain significance ★★ ⚠ same condition
COA8 p.Gln88Arg Uncertain significance ★★ ⚠ same condition

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/coa8-p-pro73his (accessed [today's date]).

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