Is P4HB p.Val28= (c.84G>A) pathogenic?

P4HB p.Val28= (c.84G>A) is classified Likely benign in P4HB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). Ultra-rare (popmax 0.0347%, mid); Associated with Cole-Carpenter syndrome 1.

What condition is associated with P4HB p.Val28= (c.84G>A)?

P4HB p.Val28= (c.84G>A) is associated with Cole-Carpenter syndrome 1 (ClinVar).

How common is P4HB p.Val28= (c.84G>A) in the general population?

P4HB p.Val28= (c.84G>A) is ultra-rare (popmax 0.0347%, mid) (gnomAD).

P4HB p.Val28=

c.84G>A · VCV3766925

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, mid)

Conditions

Cole-Carpenter syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.77, phastCons 1
Overall
CADD	14.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0347% Middle Eastern · 2/5,770 alleles

Filtering AF 0.00609% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00034% 5/1,468,876 alleles · ultra-rare exomes 5/1,316,654 · genomes 0/152,222 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0347%	2,885
South Asian	0.00132%	75,600
European (non-Finnish)	0.00018%	554,487

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: P4HB
Protein: p.Val28=
Coding: c.84G>A
MANE Select: NM_000918
Type: single nucleotide variant
Location: chr17:81860388 (GRCh38)
Gene constraint: LOEUF 0.561 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 88.62 · 14 PDB
Residue 28: the thioredoxin 1 domain; a β-strand

Full P4HB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cole-Carpenter syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

P4HB p.Val28Met Uncertain significance ★ ⚠ same residue
P4HB p.Thr110Met Uncertain significance ★★ ⚠ same condition
P4HB p.Ala144Thr Benign/Likely benign ★★ same condition
P4HB p.Thr101= Benign/Likely benign ★★ same condition
P4HB p.Tyr393Cys Pathogenic ★ same condition
P4HB c.624+3G>T Uncertain significance ★ same condition
P4HB p.Asp383Val Uncertain significance ★ same condition
P4HB p.Glu485Gln 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/p4hb-p-val28 (accessed [today's date]).

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