Is COA8 p.Pro14Thr (c.40C>A) pathogenic?

COA8 p.Pro14Thr (c.40C>A) is classified Likely benign in COA8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-08). AlphaMissense: likely benign (0.0907); Rare (popmax 0.366%, nfe).

How common is COA8 p.Pro14Thr (c.40C>A) in the general population?

COA8 p.Pro14Thr (c.40C>A) is rare (popmax 0.366%, nfe) (gnomAD).

What do computational predictors say about COA8 p.Pro14Thr (c.40C>A)?

AlphaMissense predicts likely benign (score 0.0907) — an in-silico prediction, not a clinical call.

COA8 p.Pro14Thr

c.40C>A · rs2274268 · VCV381449

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0907 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.366%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0907	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -7.24	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 -1.8	GERP -2
Regional constraint	o/e 1.16	unconstrained · MANE · 27 kb · p 0.018 · regional, not allelic
Overall
CADD	0.249	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 P27T vs ClinVar P14T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.366% European (non-Finnish) · 4,214/1,150,230 alleles

Filtering AF 0.357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.353%

Overall 0.294% 4,541/1,543,774 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.366%	273
Remaining individualsnot grpmax-eligible	0.198%	506
Admixed American	0.155%	645
African / African-American	0.0667%	1,499
Finnishnot grpmax-eligible	0.0614%	1,629
South Asian	0.0494%	2,024
Ashkenazi Jewishnot grpmax-eligible	0.014%	7,159
East Asian	0.00954%	10,480

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: COA8
Protein: p.Pro14Thr
Coding: c.40C>A
MANE Select: NM_001370595
dbSNP: rs2274268
Type: single nucleotide variant
Location: chr14:103563041 (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

Similar variants

COA8 p.Pro14His Uncertain significance ★★ ⚠ same residue
COA8 p.Pro14Ser Uncertain significance ★★ ⚠ same residue
COA8 p.Pro14Ala Benign/Likely benign ★★ same residue
COA8 p.Pro14Arg Benign/Likely benign ★★ same residue
COA8 p.Pro14Leu Uncertain significance ★ ⚠ same residue
COA8 p.Arg66Ter Pathogenic ★★ same type
COA8 c.-32C>G Uncertain significance ★★ ⚠ same type
COA8 p.Ala140Val 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/coa8-p-pro14thr (accessed [today's date]).

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