Is FCGR2A p.Ser166Phe (c.497C>T) pathogenic?

FCGR2A p.Ser166Phe (c.497C>T) is classified Uncertain significance in FCGR2A (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.2629); Very rare (popmax 0.00133%, afr); Associated with cystic fibrosis.

What condition is associated with FCGR2A p.Ser166Phe (c.497C>T)?

FCGR2A p.Ser166Phe (c.497C>T) is associated with cystic fibrosis, systemic lupus erythematosus, malaria, susceptibility to (ClinVar).

How common is FCGR2A p.Ser166Phe (c.497C>T) in the general population?

FCGR2A p.Ser166Phe (c.497C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Cystic fibrosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FCGR2A p.Ser166Phe (c.497C>T)?

AlphaMissense predicts likely benign (score 0.2629) — an in-silico prediction, not a clinical call.

FCGR2A p.Ser166Phe

c.497C>T · rs1675655979 · VCV1675085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.2629	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -1.3
Regional constraint	o/e 0.72	unconstrained · MANE · 5,367 bp · p 1e-05 · regional, not allelic
Overall
CADD	0.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00133% African / African-American · 1/75,024 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,026 alleles · very rare exomes 5/1,461,732 · genomes 0/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,024
European (non-Finnish)	0.000339%	294,978

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: FCGR2A
Protein: p.Ser166Phe
Coding: c.497C>T
MANE Select: NM_001136219
dbSNP: rs1675655979
Type: single nucleotide variant
Location: chr1:161509952 (GRCh38)
Gene constraint: LOEUF 0.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.04 · 10 PDB
Residue 166: a β-strand; the ig-like c2-type 2 domain

Full FCGR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cystic fibrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: systemic lupus erythematosus malaria, susceptibility to

For Cystic fibrosis (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

FCGR2A c.780+1G>A Uncertain significance ★★ same condition
FCGR2A p.Ser315Gly Uncertain significance ★★ ⚠ same type
FCGR2A c.365-11G>A Benign ★★ same type
FCGR2A p.Gln63Arg Benign ★★ same type
FCGR2A p.Gln63Ter Benign ★★ same type
FCGR2A p.His167Arg Benign ★★ same type
FCGR2A p.Pro215= Benign ★★ same type
FCGR2A p.Pro293= 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/fcgr2a-p-ser166phe (accessed [today's date]).

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