Is FAP p.Phe185Leu (c.553T>C) pathogenic?

FAP p.Phe185Leu (c.553T>C) is classified Likely benign in FAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-15). AlphaMissense: ambiguous (0.5265); Rare (popmax 0.899%, nfe).

How common is FAP p.Phe185Leu (c.553T>C) in the general population?

FAP p.Phe185Leu (c.553T>C) is rare (popmax 0.899%, nfe) (gnomAD).

What do computational predictors say about FAP p.Phe185Leu (c.553T>C)?

AlphaMissense predicts ambiguous (score 0.5265) — an in-silico prediction, not a clinical call.

FAP p.Phe185Leu

c.553T>C · rs78722278 · VCV782404

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5265 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.899%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5265	ambiguous
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.75 · regional, not allelic
Overall
CADD	15.07	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 0.899% European (non-Finnish) · 10,559/1,174,770 alleles

Filtering AF 0.884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.879%

Overall 0.747% 12,004/1,606,080 alleles · rare exomes 11,208/1,453,876 · genomes 796/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.899%	111
Middle Eastern	0.717%	139
Remaining individualsnot grpmax-eligible	0.647%	155
South Asian	0.445%	225
Finnishnot grpmax-eligible	0.394%	254
Admixed American	0.329%	304
Ashkenazi Jewishnot grpmax-eligible	0.146%	684
African / African-American	0.144%	693
East Asian	0.00224%	44,640

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.Phe185Leu
Coding: c.553T>C
MANE Select: NM_004460
dbSNP: rs78722278
Type: single nucleotide variant
Location: chr2:162219117 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.72 · 4 PDB

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.Ser737= Likely benign ★★ same type
FAP p.Thr229Met Benign ★★ ⚠ same type
FAP p.Tyr458= 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-phe185leu (accessed [today's date]).

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