Is FANCD2 p.Phe664= (c.1992C>T) pathogenic?

FANCD2 p.Phe664= (c.1992C>T) is classified Uncertain significance in FANCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-17). Very rare (popmax 0.00445%, eas); Associated with Fanconi anemia.

What condition is associated with FANCD2 p.Phe664= (c.1992C>T)?

FANCD2 p.Phe664= (c.1992C>T) is associated with Fanconi anemia (ClinVar).

How common is FANCD2 p.Phe664= (c.1992C>T) in the general population?

FANCD2 p.Phe664= (c.1992C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

How is Hereditary isolated aplastic anemia inherited?

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

FANCD2 p.Phe664=

c.1992C>T · VCV4739651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

Fanconi anemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.45	acceptor loss · deltas
Pangolin	Δ0.28	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.37	GERP -3.5, phastCons 1
Overall
CADD	6.933	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,902 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000558% 9/1,613,606 alleles · very rare exomes 9/1,461,398 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,451
Remaining individualsnot grpmax-eligible	0.0016%	62,456
South Asian	0.0011%	91,070
European (non-Finnish)	0.000424%	235,930

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: FANCD2
Protein: p.Phe664=
Coding: c.1992C>T
MANE Select: NM_001018115
Type: single nucleotide variant
Location: chr3:10064400 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.24 · 13 PDB

Full FANCD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Hereditary isolated aplastic anemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

FANCD2 c.1948-6C>A Pathogenic/Likely pathogenic ★★ same condition
FANCD2 c.206-1G>T Likely pathogenic ★★ same condition
FANCD2 c.2169-1G>C Likely pathogenic ★★ same condition
FANCD2 c.2269+1G>A Likely pathogenic ★★ same condition
FANCD2 c.2715+1G>A Pathogenic/Likely pathogenic ★★ same condition
FANCD2 c.3224+1G>T Likely pathogenic ★★ same condition
FANCD2 c.3467-2A>G Likely pathogenic ★★ same condition
FANCD2 c.3560+1G>A Likely pathogenic ★★ 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/fancd2-p-phe664 (accessed [today's date]).

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