Is PIGN p.Pro335Leu (c.1004C>T) pathogenic?

PIGN p.Pro335Leu (c.1004C>T) is classified Uncertain significance in PIGN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-17). AlphaMissense: ambiguous (0.4135); Very rare (popmax 0.000622%, nfe); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Pro335Leu (c.1004C>T)?

PIGN p.Pro335Leu (c.1004C>T) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Pro335Leu (c.1004C>T) in the general population?

PIGN p.Pro335Leu (c.1004C>T) is very rare (popmax 0.000622%, nfe) (gnomAD).

What do computational predictors say about PIGN p.Pro335Leu (c.1004C>T)?

AlphaMissense predicts ambiguous (score 0.4135) — an in-silico prediction, not a clinical call.

PIGN p.Pro335Leu

c.1004C>T · rs753868318 · VCV472204

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000622%, nfe)

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
AlphaMissense	0.4135	ambiguous
REVEL	0.539	indeterminate
SaProt	LLR -12.26	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	31.0	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 0.000622% European (non-Finnish) · 7/1,126,068 alleles

Filtering AF 0.000259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000454% 7/1,540,478 alleles · very rare exomes 7/1,388,454 · genomes 0/152,024 · 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: PIGN
Protein: p.Pro335Leu
Coding: c.1004C>T
MANE Select: NM_176787
dbSNP: rs753868318
Type: single nucleotide variant
Location: chr18:62140439 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.33

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

Disease context

multiple congenital anomalies-hypotonia-seizures syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PIGN p.Pro335= Likely benign ★ same residue
PIGN c.1251+1G>A Pathogenic/Likely pathogenic ★★ same condition
PIGN c.1252-2A>G Pathogenic/Likely pathogenic ★★ same condition
PIGN c.1434+5G>A Pathogenic/Likely pathogenic ★★ same condition
PIGN c.1574+1G>A Likely pathogenic ★★ same condition
PIGN c.1674+1G>A Likely pathogenic ★★ same condition
PIGN c.1674+1G>C Pathogenic ★★ same condition
PIGN c.1675-1G>T Pathogenic/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/pign-p-pro335leu (accessed [today's date]).

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