Is LAP3 p.Trp415Ser (c.1244G>C) pathogenic?

LAP3 p.Trp415Ser (c.1244G>C) is classified Uncertain significance in LAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.8351); Ultra-rare (popmax 0.011%, nfe).

How common is LAP3 p.Trp415Ser (c.1244G>C) in the general population?

LAP3 p.Trp415Ser (c.1244G>C) is ultra-rare (popmax 0.011%, nfe) (gnomAD).

What do computational predictors say about LAP3 p.Trp415Ser (c.1244G>C)?

AlphaMissense predicts likely pathogenic (score 0.8351) — an in-silico prediction, not a clinical call.

LAP3 p.Trp415Ser

c.1244G>C · rs199781902 · VCV2379992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8351	likely pathogenic
REVEL	0.577	indeterminate
SaProt	LLR -11.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 30 kb · p 0.086 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% European (non-Finnish) · 130/1,177,916 alleles

Filtering AF 0.00946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00889%

Overall 0.00869% 140/1,611,732 alleles · ultra-rare exomes 134/1,459,556 · genomes 6/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.011%	9,061
Admixed American	0.005%	19,996
Remaining individualsnot grpmax-eligible	0.00481%	20,810
Finnishnot grpmax-eligible	0.00312%	32,009
African / African-American	0.00267%	37,461

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: LAP3
Protein: p.Trp415Ser
Coding: c.1244G>C
MANE Select: NM_015907
dbSNP: rs199781902
Type: single nucleotide variant
Location: chr4:17604651 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.18

Full LAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LAP3 p.Trp415Cys Uncertain significance ★ ⚠ same residue
LAP3 p.Ala105Ser Uncertain significance ★ ⚠ same type
LAP3 p.Ala148Thr Uncertain significance ★ ⚠ same type
LAP3 p.Ala151Ser Uncertain significance ★ ⚠ same type
LAP3 p.Ala175Thr Uncertain significance ★ ⚠ same type
LAP3 p.Ala199Gly Uncertain significance ★ same type
LAP3 p.Ala244Thr Uncertain significance ★ ⚠ same type
LAP3 p.Ala30Thr Uncertain significance ★ ⚠ 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/lap3-p-trp415ser (accessed [today's date]).

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