Is FPR2 p.Phe74Leu (c.220T>C) pathogenic?

FPR2 p.Phe74Leu (c.220T>C) is classified Benign/Likely benign in FPR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-01). AlphaMissense: likely pathogenic (0.9694); Rare (popmax 0.682%, nfe).

How common is FPR2 p.Phe74Leu (c.220T>C) in the general population?

FPR2 p.Phe74Leu (c.220T>C) is rare (popmax 0.682%, nfe) (gnomAD).

What do computational predictors say about FPR2 p.Phe74Leu (c.220T>C)?

AlphaMissense predicts likely pathogenic (score 0.9694) — an in-silico prediction, not a clinical call.

FPR2 p.Phe74Leu

c.220T>C · rs74602258 · VCV781747

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9694 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.682%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9694	likely pathogenic · top 2% in FPR2
REVEL	0.462	indeterminate
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,052 bp · p 0.0023 · regional, not allelic
Overall
CADD	23.1	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 0.682% European (non-Finnish) · 8,053/1,180,026 alleles

Filtering AF 0.67% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.665%

Overall 0.59% 9,526/1,614,192 alleles · rare exomes 8,860/1,461,894 · genomes 666/152,298 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.48%	68
European (non-Finnish)grpmax	0.682%	147
Remaining individualsnot grpmax-eligible	0.514%	195
Ashkenazi Jewishnot grpmax-eligible	0.186%	538
Admixed American	0.142%	706
African / African-American	0.0773%	1,294
South Asian	0.00769%	13,012
East Asian	0.00223%	44,876

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FPR2
Protein: p.Phe74Leu
Coding: c.220T>C
MANE Select: NM_001005738
dbSNP: rs74602258
Type: single nucleotide variant
Location: chr19:51768878 (GRCh38)
Gene constraint: LOEUF 1.667 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 13 PDB
Residue 74: an α-helix

Full FPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FPR2 c.-15+1402C>T Uncertain significance ★ same type
FPR2 p.Ala245Val Uncertain significance ★ ⚠ same type
FPR2 p.Ala248Ser Uncertain significance ★ ⚠ same type
FPR2 p.Arg137Cys Uncertain significance ★ same type
FPR2 p.Arg57Cys Uncertain significance ★ ⚠ same type
FPR2 p.Arg57His Uncertain significance ★ ⚠ same type
FPR2 p.Cys296Trp Uncertain significance ★ ⚠ same type
FPR2 p.Cys98Arg 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/fpr2-p-phe74leu (accessed [today's date]).

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