Is COXFA4L2 p.Pro58Ser (c.172C>T) pathogenic?

COXFA4L2 p.Pro58Ser (c.172C>T) is classified Uncertain significance in COXFA4L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.9279); Ultra-rare (popmax 0.0173%, mid).

How common is COXFA4L2 p.Pro58Ser (c.172C>T) in the general population?

COXFA4L2 p.Pro58Ser (c.172C>T) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about COXFA4L2 p.Pro58Ser (c.172C>T)?

AlphaMissense predicts likely pathogenic (score 0.9279) — an in-silico prediction, not a clinical call.

COXFA4L2 p.Pro58Ser

c.172C>T · VCV3918346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9279 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9279	likely pathogenic · top 7% in COXFA4L2
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -13.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,519 bp · p 0.24 · regional, not allelic
Overall
CADD	28.1	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

Grpmax group 0.0173% Middle Eastern · 1/5,784 alleles

Filtering AF 0.000299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000216%

Overall 0.000576% 9/1,563,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,784
European (non-Finnish)	0.000695%	143,906

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: COXFA4L2
Protein: p.Pro58Ser
Coding: c.172C>T
MANE Select: NM_001394961
Type: single nucleotide variant
Location: chr12:57235784 (GRCh38)
Structure: AlphaFold pLDDT 84.56

Full COXFA4L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COXFA4L2 p.Arg61Cys Uncertain significance ★ ⚠ same type
COXFA4L2 p.Arg61His Uncertain significance ★ ⚠ same type
COXFA4L2 p.Leu39Val Uncertain significance ★ ⚠ same type
COXFA4L2 p.Leu80Pro Uncertain significance ★ ⚠ same type
NDUFA4L2 p.Arg12Gly Uncertain significance ★ ⚠ same type
NDUFA4L2 p.Arg12Trp Uncertain significance ★ ⚠ same type
NDUFA4L2 p.Arg61Leu Uncertain significance ★ ⚠ same type
NDUFA4L2 p.Arg9His 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/coxfa4l2-p-pro58ser (accessed [today's date]).

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