Is PEX16 p.Pro140His (c.419C>A) pathogenic?

PEX16 p.Pro140His (c.419C>A) is classified Uncertain significance in PEX16 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.921); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PEX16 p.Pro140His (c.419C>A)?

PEX16 p.Pro140His (c.419C>A) is associated with Inborn genetic diseases, peroxisome biogenesis disorder (ClinVar).

How common is PEX16 p.Pro140His (c.419C>A) in the general population?

PEX16 p.Pro140His (c.419C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX16 p.Pro140His (c.419C>A)?

AlphaMissense predicts likely pathogenic (score 0.921) — an in-silico prediction, not a clinical call.

PEX16 p.Pro140His

c.419C>A · rs764641368 · VCV2038279

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.921 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.921	likely pathogenic · top 10% in PEX16
REVEL	0.473	indeterminate
SaProt	LLR -5.35	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,554 bp · p 0.075 · regional, not allelic
Overall
CADD	27.9	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

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: PEX16
Protein: p.Pro140His
Coding: c.419C>A
MANE Select: NM_004813
dbSNP: rs764641368
Type: single nucleotide variant
Location: chr11:45915509 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.07

Full PEX16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder

Similar variants

PEX16 p.Pro140Arg Uncertain significance ★★ ⚠ same residue
PEX16 p.Pro140Ala Uncertain significance ★ ⚠ same residue
PEX16 p.Pro140Thr Uncertain significance ★ ⚠ same residue
PEX16 c.888-1G>C Likely pathogenic ★★ same condition
PEX16 p.Arg176Ter Pathogenic ★★ same condition
PEX16 p.Arg227Trp Likely pathogenic ★★ same condition
PEX16 p.Arg287Cys Pathogenic/Likely pathogenic ★★ same condition
PEX16 p.Arg287His Pathogenic/Likely pathogenic ★★ ⚠ 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/pex16-p-pro140his (accessed [today's date]).

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