Is PEX5 p.Val227Ala (c.680T>C) pathogenic?

PEX5 p.Val227Ala (c.680T>C) is classified Uncertain significance in PEX5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-18). AlphaMissense: likely benign (0.3024); Ultra-rare (popmax 0.0267%, afr); Associated with Inborn genetic diseases.

What condition is associated with PEX5 p.Val227Ala (c.680T>C)?

PEX5 p.Val227Ala (c.680T>C) is associated with Inborn genetic diseases, peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Val227Ala (c.680T>C) in the general population?

PEX5 p.Val227Ala (c.680T>C) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about PEX5 p.Val227Ala (c.680T>C)?

AlphaMissense predicts likely benign (score 0.3024) — an in-silico prediction, not a clinical call.

PEX5 p.Val227Ala

c.680T>C · rs777842778 · VCV445968

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3024 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3024	likely benign
REVEL	0.504	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0267% African / African-American · 20/75,034 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00136% 22/1,614,122 alleles · ultra-rare exomes 6/1,461,888 · genomes 16/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,752
Admixed American	0.00167%	60,018
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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: PEX5
Protein: p.Val227Ala
Coding: c.680T>C
MANE Select: NM_001351132
dbSNP: rs777842778
Type: single nucleotide variant
Location: chr12:7202278 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB

Full PEX5 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 2B

Similar variants

PEX5 p.Val227= Likely benign ★ same residue
PEX5 c.449-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.552-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.847-2A>G Likely pathogenic ★★ same condition
PEX5 c.967-1G>A Likely pathogenic ★★ same condition
PEX5 p.Arg237Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg276Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg420Ter 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/pex5-p-val227ala (accessed [today's date]).

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