Is PEX7 p.Val185Ala (c.554T>C) pathogenic?

PEX7 p.Val185Ala (c.554T>C) is classified Uncertain significance in PEX7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-02-10). AlphaMissense: likely benign (0.1237); Very rare (popmax 0.005%, amr); Associated with peroxisome biogenesis disorder 9B.

What condition is associated with PEX7 p.Val185Ala (c.554T>C)?

PEX7 p.Val185Ala (c.554T>C) is associated with peroxisome biogenesis disorder 9B, rhizomelic chondrodysplasia punctata type 1, adult Refsum disease (ClinVar).

How common is PEX7 p.Val185Ala (c.554T>C) in the general population?

PEX7 p.Val185Ala (c.554T>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PEX7 p.Val185Ala (c.554T>C)?

AlphaMissense predicts likely benign (score 0.1237) — an in-silico prediction, not a clinical call.

PEX7 p.Val185Ala

c.554T>C · rs1424846175 · VCV904199

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 9B

Computational evidence

Protein change
AlphaMissense	0.1237	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -7.15	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 1.5	GERP -0.8, phastCons 0.98
Regional constraint	o/e 0.98	unconstrained · MANE · 91 kb · p 0.75 · regional, not allelic
Overall
CADD	18.9	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 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,614,078 alleles · very rare exomes 3/1,461,748 · genomes 0/152,330 · joint denominator

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: PEX7
Protein: p.Val185Ala
Coding: c.554T>C
MANE Select: NM_000288
dbSNP: rs1424846175
Type: single nucleotide variant
Location: chr6:136866654 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.54

Full PEX7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 9B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: rhizomelic chondrodysplasia punctata type 1 adult Refsum disease

Similar variants

PEX7 c.130+1G>A Pathogenic ★★ same condition
PEX7 c.131-1G>A Likely pathogenic ★★ same condition
PEX7 c.188+1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX7 c.188+1G>C Pathogenic/Likely pathogenic ★★ same condition
PEX7 c.340-1G>T Likely pathogenic ★★ same condition
PEX7 c.634-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX7 c.748-2A>G Likely pathogenic ★★ same condition
PEX7 c.803+1G>A 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/pex7-p-val185ala (accessed [today's date]).

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