Is FAP p.Leu494Ser (c.1481T>C) pathogenic?

FAP p.Leu494Ser (c.1481T>C) is classified Uncertain significance in FAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.8871); Very rare (popmax 0.00676%, afr).

How common is FAP p.Leu494Ser (c.1481T>C) in the general population?

FAP p.Leu494Ser (c.1481T>C) is very rare (popmax 0.00676%, afr) (gnomAD).

What do computational predictors say about FAP p.Leu494Ser (c.1481T>C)?

AlphaMissense predicts likely pathogenic (score 0.8871) — an in-silico prediction, not a clinical call.

FAP p.Leu494Ser

c.1481T>C · VCV4022914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00676%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8871	likely pathogenic
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -11.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.75 · regional, not allelic
Overall
CADD	26.9	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 0.00676% African / African-American · 5/73,934 alleles

Filtering AF 0.00258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.000315% 5/1,588,152 alleles · very rare

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: FAP
Protein: p.Leu494Ser
Coding: c.1481T>C
MANE Select: NM_004460
Type: single nucleotide variant
Location: chr2:162189724 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.72 · 4 PDB
Residue 494: an α-helix

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

Similar variants

FAP c.1870-8C>A Benign ★★ same type
FAP p.Ala100= Benign ★★ same type
FAP p.Gln708= Benign ★★ same type
FAP p.Gly195= Benign ★★ same type
FAP p.Leu212Phe Benign ★★ ⚠ same type
FAP p.Phe185Leu Likely benign ★★ ⚠ same type
FAP p.Ser737= Likely benign ★★ same type
FAP p.Thr229Met 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/fap-p-leu494ser (accessed [today's date]).

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