Is COX4I2 p.Ala59Pro (c.175G>C) pathogenic?

COX4I2 p.Ala59Pro (c.175G>C) is classified Conflicting classifications of pathogenicity in COX4I2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0988); Rare (popmax 0.287%, afr); Associated with pancreatic insufficiency-anemia-hyperostosis syndrome.

What condition is associated with COX4I2 p.Ala59Pro (c.175G>C)?

COX4I2 p.Ala59Pro (c.175G>C) is associated with pancreatic insufficiency-anemia-hyperostosis syndrome (ClinVar).

How common is COX4I2 p.Ala59Pro (c.175G>C) in the general population?

COX4I2 p.Ala59Pro (c.175G>C) is rare (popmax 0.287%, afr) (gnomAD).

What do computational predictors say about COX4I2 p.Ala59Pro (c.175G>C)?

AlphaMissense predicts likely benign (score 0.0988) — an in-silico prediction, not a clinical call.

COX4I2 p.Ala59Pro

Q: How is Pancreatic insufficiency-anemia-hyperostosis syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.175G>C · rs147223483 · VCV1032977

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0988 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.287%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pancreatic insufficiency-anemia-hyperostosis syndrome

Computational evidence

Protein change
AlphaMissense	0.0988	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -6.93	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 3.6	GERP 2.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,883 bp · p 0.94 · regional, not allelic
Overall
CADD	16.31	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.287% African / African-American · 215/75,012 alleles

Filtering AF 0.255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.243%

Overall 0.016% 259/1,613,928 alleles · rare exomes 120/1,461,702 · genomes 139/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.287%	349
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Admixed American	0.025%	4,000
Middle Eastern	0.0165%	6,062
South Asian	0.00439%	22,771

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: COX4I2
Protein: p.Ala59Pro
Coding: c.175G>C
MANE Select: NM_032609
dbSNP: rs147223483
Type: single nucleotide variant
Location: chr20:31640025 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84

Full COX4I2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pancreatic insufficiency-anemia-hyperostosis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pancreatic insufficiency-anemia-hyperostosis syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COX4I2 p.Glu138Lys Uncertain significance ★★ ⚠ same condition
COX4I2 p.Val10Met Uncertain significance ★★ ⚠ same condition
COX4I2 p.Gly30Arg Benign/Likely benign ★★ same condition
COX4I2 p.Thr136= Likely benign ★★ same condition
COX4I2 p.Phe111Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
COX4I2 p.Ala117fs Uncertain significance ★ same condition
COX4I2 p.Arg161Cys Uncertain significance ★★ ⚠ same type
COX4I2 p.Arg29His 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/cox4i2-p-ala59pro (accessed [today's date]).

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