Is LRPAP1 p.Ala264Val (c.791C>T) pathogenic?

LRPAP1 p.Ala264Val (c.791C>T) is classified Uncertain significance in LRPAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: ambiguous (0.5054); Very rare (popmax 0.00914%, amr).

How common is LRPAP1 p.Ala264Val (c.791C>T) in the general population?

LRPAP1 p.Ala264Val (c.791C>T) is very rare (popmax 0.00914%, amr) (gnomAD).

What do computational predictors say about LRPAP1 p.Ala264Val (c.791C>T)?

AlphaMissense predicts ambiguous (score 0.5054) — an in-silico prediction, not a clinical call.

LRPAP1 p.Ala264Val

c.791C>T · VCV4099995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00914%, amr)

Computational evidence

Protein change
AlphaMissense	0.5054	ambiguous
REVEL	0.611	indeterminate
SaProt	LLR -6.22	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 19 kb · p 0.00017 · regional, not allelic
Overall
CADD	26.1	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 0.00914% Admixed American · 5/54,676 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00234%

Overall 0.00221% 35/1,582,404 alleles · very rare exomes 29/1,430,162 · genomes 6/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00914%	10,935
African / African-American	0.00671%	14,913
Remaining individualsnot grpmax-eligible	0.00326%	30,682
European (non-Finnish)	0.00189%	52,946
South Asian	0.00116%	86,392

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: LRPAP1
Protein: p.Ala264Val
Coding: c.791C>T
MANE Select: NM_002337
Type: single nucleotide variant
Location: chr4:3516159 (GRCh38)
Gene constraint: LOEUF 1.375 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.80 · 10 PDB
Residue 264: the 'ldl receptor binding' region; an α-helix

Full LRPAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRPAP1 p.Ala264Ser Uncertain significance ★ ⚠ same residue
LRPAP1 p.Arg110Thr Uncertain significance ★★ ⚠ same type
LRPAP1 p.Ala109= Benign/Likely benign ★★ same type
LRPAP1 p.Asp211Asn Likely benign ★★ same type
LRPAP1 p.Gly166= Benign ★★ same type
LRPAP1 p.Gly166Ser Benign/Likely benign ★★ same type
LRPAP1 p.Ile199Val Benign ★★ same type
LRPAP1 c.751+1G>A Likely pathogenic ★ 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/lrpap1-p-ala264val (accessed [today's date]).

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