Is PIGN p.Val417Met (c.1249G>A) pathogenic?

PIGN p.Val417Met (c.1249G>A) is classified Uncertain significance in PIGN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-23). AlphaMissense: likely benign (0.2057); Very rare (popmax 0.00277%, afr); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

What condition is associated with PIGN p.Val417Met (c.1249G>A)?

PIGN p.Val417Met (c.1249G>A) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 1 (ClinVar).

How common is PIGN p.Val417Met (c.1249G>A) in the general population?

PIGN p.Val417Met (c.1249G>A) is very rare (popmax 0.00277%, afr) (gnomAD).

What do computational predictors say about PIGN p.Val417Met (c.1249G>A)?

AlphaMissense predicts likely benign (score 0.2057) — an in-silico prediction, not a clinical call.

PIGN p.Val417Met

c.1249G>A · rs762619265 · VCV1505045

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00277%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2057	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 109 kb · p 0.83 · regional, not allelic
Overall
CADD	20.9	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 0.00277% African / African-American · 2/72,298 alleles

Filtering AF 0.000459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000172%

Overall 0.000531% 8/1,505,560 alleles · very rare exomes 6/1,353,578 · genomes 2/151,982 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00277%	36,149
European (non-Finnish)	0.000543%	184,188

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.Val417Met
Coding: c.1249G>A
MANE Select: NM_176787
dbSNP: rs762619265
Type: single nucleotide variant
Location: chr18:62114563 (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 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
PIGN c.222-1G>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/pign-p-val417met (accessed [today's date]).

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