Is FAP p.Pro147Leu (c.440C>T) pathogenic?

FAP p.Pro147Leu (c.440C>T) is classified Uncertain significance in FAP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-15). AlphaMissense: ambiguous (0.369); Very rare (popmax 0.00237%, nfe).

How common is FAP p.Pro147Leu (c.440C>T) in the general population?

FAP p.Pro147Leu (c.440C>T) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about FAP p.Pro147Leu (c.440C>T)?

AlphaMissense predicts ambiguous (score 0.369) — an in-silico prediction, not a clinical call.

FAP p.Pro147Leu

c.440C>T · rs138190509 · VCV2394337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Computational evidence

Protein change
AlphaMissense	0.369	ambiguous
REVEL	0.439	indeterminate
SaProt	LLR -11.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,178,952 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,612,394 alleles · very rare exomes 28/1,460,396 · genomes 1/151,998 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,105
Remaining individualsnot grpmax-eligible	0.0016%	62,416

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.Pro147Leu
Coding: c.440C>T
MANE Select: NM_004460
dbSNP: rs138190509
Type: single nucleotide variant
Location: chr2:162219899 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.72 · 4 PDB
Residue 147: an α-helix

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

Similar variants

FAP p.Pro147Thr Uncertain significance ★ same residue
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

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-pro147leu (accessed [today's date]).

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