Is PEX14 p.Ala74= (c.222C>T) pathogenic?

PEX14 p.Ala74= (c.222C>T) is classified Conflicting classifications of pathogenicity in PEX14 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0936%, eas); Associated with peroxisome biogenesis disorder, complementation group K.

What condition is associated with PEX14 p.Ala74= (c.222C>T)?

PEX14 p.Ala74= (c.222C>T) is associated with peroxisome biogenesis disorder, complementation group K (ClinVar).

How common is PEX14 p.Ala74= (c.222C>T) in the general population?

PEX14 p.Ala74= (c.222C>T) is ultra-rare (popmax 0.0936%, eas) (gnomAD).

PEX14 p.Ala74=

c.222C>T · rs147043673 · VCV595983

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0936%, eas)

Conditions

peroxisome biogenesis disorder, complementation group K

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.4	GERP -5.7
Overall
CADD	2.77	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0936% East Asian · 42/44,882 alleles

Filtering AF 0.0712% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0632%

Overall 0.00632% 102/1,613,870 alleles · ultra-rare exomes 71/1,461,542 · genomes 31/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0936%	1,069
African / African-American	0.0413%	2,421
Middle Eastern	0.0165%	6,062
South Asian	0.0165%	6,072
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Admixed American	0.00333%	30,015
European (non-Finnish)	0.000593%	168,532

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: PEX14
Protein: p.Ala74=
Coding: c.222C>T
MANE Select: NM_004565
dbSNP: rs147043673
Type: single nucleotide variant
Location: chr1:10599290 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.91 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.48 · 4 PDB

Full PEX14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder, complementation group K — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX14 c.36+6G>T Uncertain significance ★★ same condition
PEX14 p.Ala102Thr Uncertain significance ★★ ⚠ same condition
PEX14 p.Ala254Val Uncertain significance ★★ ⚠ same condition
PEX14 p.Ala370Ser Uncertain significance ★★ ⚠ same condition
PEX14 p.Arg105Gln Uncertain significance ★★ ⚠ same condition
PEX14 p.Arg139Leu Uncertain significance ★★ ⚠ same condition
PEX14 p.Arg142Lys Uncertain significance ★★ ⚠ same condition
PEX14 p.Arg350Cys Uncertain significance ★★ ⚠ same condition

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/pex14-p-ala74 (accessed [today's date]).

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