Is ALPP p.Val376Leu (c.1126G>C) pathogenic?

ALPP p.Val376Leu (c.1126G>C) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.5); Very rare (popmax 0.00726%, nfe).

How common is ALPP p.Val376Leu (c.1126G>C) in the general population?

ALPP p.Val376Leu (c.1126G>C) is very rare (popmax 0.00726%, nfe) (gnomAD).

What do computational predictors say about ALPP p.Val376Leu (c.1126G>C)?

AlphaMissense predicts ambiguous (score 0.5) — an in-silico prediction, not a clinical call.

ALPP p.Val376Leu

c.1126G>C · VCV4640121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00726%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5	ambiguous
REVEL	0.721	pathogenic-leaning
SaProt	LLR -12.34	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39
Regional constraint	o/e 0.01	constrained · MANE · 594 bp · p 1.9e-31 · regional, not allelic
Overall
CADD	18.3	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 0.00726% European (non-Finnish) · 81/1,115,886 alleles

Filtering AF 0.00595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00544%

Overall 0.00592% 89/1,503,286 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00726%	13,776
Remaining individualsnot grpmax-eligible	0.00688%	14,545
Admixed American	0.004%	24,970
African / African-American	0.00282%	35,456

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: ALPP
Protein: p.Val376Leu
Coding: c.1126G>C
MANE Select: NM_001632
Type: single nucleotide variant
Location: chr2:232380965 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB
Residue 376: a β-strand

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

Similar variants

ALPP c.865+8C>T Likely benign ★★ same type
ALPP p.Ala176= Benign ★★ same type
ALPP p.Arg231Pro Benign ★★ same type
ALPP p.Arg36= Benign ★★ same type
ALPP p.Glu37Gln Benign ★★ same type
ALPP p.Gly233= Likely benign ★★ same type
ALPP p.Gly63= Likely benign ★★ same type
ALPP p.Phe331= 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/alpp-p-val376leu (accessed [today's date]).

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