Is PEPD p.Arg431His (c.1292G>A) pathogenic?

PEPD p.Arg431His (c.1292G>A) is classified Uncertain significance in PEPD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-25). AlphaMissense: likely benign (0.142); Ultra-rare (popmax 0.0173%, amr); Associated with prolidase deficiency.

What condition is associated with PEPD p.Arg431His (c.1292G>A)?

PEPD p.Arg431His (c.1292G>A) is associated with prolidase deficiency (ClinVar).

How common is PEPD p.Arg431His (c.1292G>A) in the general population?

PEPD p.Arg431His (c.1292G>A) is ultra-rare (popmax 0.0173%, amr) (gnomAD).

How is Prolidase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PEPD p.Arg431His (c.1292G>A)?

AlphaMissense predicts likely benign (score 0.142) — an in-silico prediction, not a clinical call.

PEPD p.Arg431His

c.1292G>A · rs763642654 · VCV328792

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

prolidase deficiency

Computational evidence

Protein change
AlphaMissense	0.142	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -5.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.71, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	20.8	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 0.0173% Admixed American · 10/57,694 alleles

Filtering AF 0.00933% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00263% 42/1,597,322 alleles · ultra-rare exomes 33/1,445,130 · genomes 9/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0173%	5,769
East Asian	0.00679%	14,736
South Asian	0.00566%	17,682
African / African-American	0.00401%	24,915
Finnishnot grpmax-eligible	0.00163%	61,394
European (non-Finnish)	0.00162%	61,726
Remaining individualsnot grpmax-eligible	0.00162%	61,834

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: PEPD
Protein: p.Arg431His
Coding: c.1292G>A
MANE Select: NM_000285
dbSNP: rs763642654
Type: single nucleotide variant
Location: chr19:33387942 (GRCh38)
Gene constraint: LOEUF 1.132 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.62 · 21 PDB
Residue 431: an α-helix

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

Disease context

prolidase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Prolidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal

Similar variants

PEPD p.Arg431Cys Uncertain significance ★★ ⚠ same residue
PEPD p.Arg431Ser Uncertain significance ★★ ⚠ same residue
PEPD p.Arg431Pro Uncertain significance ★ ⚠ same residue
PEPD p.Arg431= Likely benign ★ same residue
PEPD c.442-1G>C Pathogenic/Likely pathogenic ★★ same condition
PEPD c.504-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEPD c.549-1G>A Pathogenic ★★ same condition
PEPD c.819-1G>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/pepd-p-arg431his (accessed [today's date]).

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