Is LPP p.Val423Ile (c.1267G>A) pathogenic?

LPP p.Val423Ile (c.1267G>A) is classified Uncertain significance in LPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: ambiguous (0.3937); Ultra-rare (popmax 0.0329%, mid).

How common is LPP p.Val423Ile (c.1267G>A) in the general population?

LPP p.Val423Ile (c.1267G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about LPP p.Val423Ile (c.1267G>A)?

AlphaMissense predicts ambiguous (score 0.3937) — an in-silico prediction, not a clinical call.

LPP p.Val423Ile

c.1267G>A · VCV4048254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3937 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Computational evidence

Protein change
AlphaMissense	0.3937	ambiguous
REVEL	0.44	indeterminate
SaProt	LLR -8.36	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	29.4	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 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00149% 24/1,613,914 alleles · ultra-rare exomes 15/1,461,824 · genomes 9/152,090 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
African / African-American	0.012%	8,318
South Asian	0.0011%	91,076
European (non-Finnish)	0.00102%	98,334

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: LPP
Protein: p.Val423Ile
Coding: c.1267G>A
MANE Select: NM_001375462
Type: single nucleotide variant
Location: chr3:188760139 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 423: the lim zinc-binding 1 domain

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

Similar variants

LPP p.Arg140Trp Uncertain significance ★★ ⚠ same type
LPP c.1113+51T>C Benign ★★ same type
LPP c.1240+249G>A Benign ★★ same type
LPP c.1240+75A>G Benign ★★ same type
LPP c.1410+155C>T Benign ★★ same type
LPP c.1410+157T>C Benign ★★ same type
LPP c.1410+162G>A Benign ★★ same type
LPP c.1410+165T>C Benign ★★ same type

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/lpp-p-val423ile (accessed [today's date]).

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