Is COX19 p.Pro16Ser (c.46C>T) pathogenic?

COX19 p.Pro16Ser (c.46C>T) is classified Uncertain significance in COX19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.2795); Very rare (popmax 0.0023%, eas).

How common is COX19 p.Pro16Ser (c.46C>T) in the general population?

COX19 p.Pro16Ser (c.46C>T) is very rare (popmax 0.0023%, eas) (gnomAD).

What do computational predictors say about COX19 p.Pro16Ser (c.46C>T)?

AlphaMissense predicts likely benign (score 0.2795) — an in-silico prediction, not a clinical call.

COX19 p.Pro16Ser

c.46C>T · VCV4233005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2795	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -8.68	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 6.8	GERP 7.8, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 6,128 bp · p 0.0099 · regional, not allelic
Overall
CADD	24.1	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 0.0023% East Asian · 1/43,412 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000687% 11/1,601,750 alleles · very rare exomes 9/1,449,478 · genomes 2/152,272 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0023%	43,412
Remaining individualsnot grpmax-eligible	0.00161%	62,036
European (non-Finnish)	0.000765%	130,636

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: COX19
Protein: p.Pro16Ser
Coding: c.46C>T
MANE Select: NM_001031617
Type: single nucleotide variant
Location: chr7:975464 (GRCh38)
Gene constraint: LOEUF 1.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.23
Residue 16: the 'disordered' region

Full COX19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX19 p.Ala49Gly Uncertain significance ★ ⚠ same type
COX19 p.Asn43Lys Uncertain significance ★ ⚠ same type
COX19 p.Asn44Ser Uncertain significance ★ ⚠ same type
COX19 p.Asn6Ser Uncertain significance ★ ⚠ same type
COX19 p.Asp25His Uncertain significance ★ ⚠ same type
COX19 p.Asp25Tyr Uncertain significance ★ ⚠ same type
COX19 p.Cys40Arg Uncertain significance ★ ⚠ same type
COX19 p.Glu60Gln 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/cox19-p-pro16ser (accessed [today's date]).

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