Is PEX16 p.Pro212Arg (c.635C>G) pathogenic?

PEX16 p.Pro212Arg (c.635C>G) is classified Benign/Likely benign in PEX16 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.0917); Rare (popmax 0.256%, eas); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX16 p.Pro212Arg (c.635C>G)?

PEX16 p.Pro212Arg (c.635C>G) is associated with peroxisome biogenesis disorder, microcephaly (ClinVar).

How common is PEX16 p.Pro212Arg (c.635C>G) in the general population?

PEX16 p.Pro212Arg (c.635C>G) is rare (popmax 0.256%, eas) (gnomAD).

What do computational predictors say about PEX16 p.Pro212Arg (c.635C>G)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

PEX16 p.Pro212Arg

c.635C>G · rs201846257 · VCV793195

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.256%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -6.56	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 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,554 bp · p 0.075 · regional, not allelic
Overall
CADD	23.3	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 0.256% East Asian · 115/44,890 alleles

Filtering AF 0.218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.204%

Overall 0.00993% 160/1,610,894 alleles · rare exomes 138/1,458,540 · genomes 22/152,354 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.256%	390
South Asian	0.0242%	4,140
Remaining individualsnot grpmax-eligible	0.024%	4,165
Middle Eastern	0.0165%	6,062
African / African-American	0.00266%	37,530
European (non-Finnish)	0.000424%	236,003

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: PEX16
Protein: p.Pro212Arg
Coding: c.635C>G
MANE Select: NM_004813
dbSNP: rs201846257
Type: single nucleotide variant
Location: chr11:45914375 (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

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

Also linked: microcephaly

Similar variants

PEX16 p.Pro212Leu Uncertain significance ★ ⚠ same residue
PEX16 p.Pro212= Likely benign ★ 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
PEX16 c.225+3G>A 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/pex16-p-pro212arg (accessed [today's date]).

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