Is FANCF p.Arg216Pro (c.647G>C) pathogenic?

FANCF p.Arg216Pro (c.647G>C) is classified Uncertain significance in FANCF (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0642); Ultra-rare (popmax 0.0976%, amr); Associated with Fanconi anemia complementation group F.

What condition is associated with FANCF p.Arg216Pro (c.647G>C)?

FANCF p.Arg216Pro (c.647G>C) is associated with Fanconi anemia complementation group F, Fanconi anemia (ClinVar).

How common is FANCF p.Arg216Pro (c.647G>C) in the general population?

FANCF p.Arg216Pro (c.647G>C) is ultra-rare (popmax 0.0976%, amr) (gnomAD).

What do computational predictors say about FANCF p.Arg216Pro (c.647G>C)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

FANCF p.Arg216Pro

c.647G>C · rs192534185 · VCV435150

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0976%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia complementation group F

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -4.63	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 0.38	GERP -2.5
Regional constraint	o/e 1.15	unconstrained · MANE · 1,121 bp · p 0.0014 · regional, not allelic
Overall
CADD	9.6	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 0.0976% Admixed American · 58/59,410 alleles

Filtering AF 0.0775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0703%

Overall 0.0133% 214/1,608,410 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0976%	1,024
Middle Eastern	0.0667%	1,500
Remaining individualsnot grpmax-eligible	0.0209%	4,780
European (non-Finnish)	0.0117%	8,527
African / African-American	0.00134%	74,716

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: FANCF
Protein: p.Arg216Pro
Coding: c.647G>C
MANE Select: NM_022725
dbSNP: rs192534185
Type: single nucleotide variant
Location: chr11:22625164 (GRCh38)
Structure: AlphaFold pLDDT 78.87 · 7 PDB

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

Disease context

Fanconi anemia complementation group F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia

Similar variants

FANCF p.Gln65Ter Likely pathogenic ★★ same condition
FANCF p.Glu220Ter Pathogenic/Likely pathogenic ★★ same condition
FANCF p.Glu223Ter Pathogenic/Likely pathogenic ★★ same condition
FANCF p.Met1Arg Pathogenic/Likely pathogenic ★★ same condition
FANCF c.-21A>G Uncertain significance ★★ same condition
FANCF c.-31T>C Uncertain significance ★★ same condition
FANCF c.*1879T>C Uncertain significance ★★ same condition
FANCF p.Ala124Ser Uncertain significance ★★ ⚠ same condition

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/fancf-p-arg216pro (accessed [today's date]).

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