Is COX16 p.Arg34His (c.101G>A) pathogenic?

COX16 p.Arg34His (c.101G>A) is classified Uncertain significance in COX16 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.2483); Very rare (popmax 0.00773%, sas).

How common is COX16 p.Arg34His (c.101G>A) in the general population?

COX16 p.Arg34His (c.101G>A) is very rare (popmax 0.00773%, sas) (gnomAD).

What do computational predictors say about COX16 p.Arg34His (c.101G>A)?

AlphaMissense predicts likely benign (score 0.2483) — an in-silico prediction, not a clinical call.

COX16 p.Arg34His

c.101G>A · rs573618970 · VCV2519096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2483 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00773%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2483	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -2.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.75 · regional, not allelic
Overall
CADD	29.0	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 0.00773% South Asian · 7/90,594 alleles

Filtering AF 0.0036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00256%

Overall 0.00161% 26/1,612,850 alleles · very rare exomes 24/1,460,718 · genomes 2/152,132 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00773%	12,942
Remaining individualsnot grpmax-eligible	0.0032%	31,224
African / African-American	0.00267%	37,421
European (non-Finnish)	0.00127%	78,647

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: COX16
Protein: p.Arg34His
Coding: c.101G>A
MANE Select: NM_016468
dbSNP: rs573618970
Type: single nucleotide variant
Location: chr14:70342698 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.50

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.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
COX16 p.Lys14Thr 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-arg34his (accessed [today's date]).

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