Is COX16 p.Pro84Leu (c.251C>T) pathogenic?

COX16 p.Pro84Leu (c.251C>T) is classified Uncertain significance in COX16 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely pathogenic (0.6152); Absent from gnomAD v4.1.

How common is COX16 p.Pro84Leu (c.251C>T) in the general population?

COX16 p.Pro84Leu (c.251C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COX16 p.Pro84Leu (c.251C>T)?

AlphaMissense predicts likely pathogenic (score 0.6152) — an in-silico prediction, not a clinical call.

COX16 p.Pro84Leu

c.251C>T · rs2504455734 · VCV3076449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6152 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6152	likely pathogenic
REVEL	0.375	indeterminate
SaProt	LLR -14.93	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.75 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: COX16
Protein: p.Pro84Leu
Coding: c.251C>T
MANE Select: NM_016468
dbSNP: rs2504455734
Type: single nucleotide variant
Location: chr14:70326403 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.50
Residue 84: the 'disordered' region; a UniProt-annotated variant site (in mc4dn22; isolated complex iv deficiency in homozygous patient cells)

Full COX16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX16 p.Ser62Pro Uncertain significance ★★ ⚠ same type
COX16 c.141+10A>G Uncertain significance ★ same type
COX16 p.Arg11Leu Uncertain significance ★ ⚠ same type
COX16 p.Arg34His Uncertain significance ★ ⚠ same type
COX16 p.Asn80Asp Uncertain significance ★ ⚠ same type
COX16 p.Gly17Ser Uncertain significance ★ ⚠ same type
COX16 p.Ile70Met Uncertain significance ★ ⚠ same type
COX16 p.Leu56Met 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/cox16-p-pro84leu (accessed [today's date]).

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