Is FANCD2 p.Ser564Phe (c.1691C>T) pathogenic?

FANCD2 p.Ser564Phe (c.1691C>T) is classified Uncertain significance in FANCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-25). AlphaMissense: ambiguous (0.537); Very rare (popmax 0.000847%, nfe).

How common is FANCD2 p.Ser564Phe (c.1691C>T) in the general population?

FANCD2 p.Ser564Phe (c.1691C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about FANCD2 p.Ser564Phe (c.1691C>T)?

AlphaMissense predicts ambiguous (score 0.537) — an in-silico prediction, not a clinical call.

FANCD2 p.Ser564Phe

c.1691C>T · VCV4087813

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Computational evidence

Protein change
AlphaMissense	0.537	ambiguous
REVEL	0.297	indeterminate
SaProt	LLR -6.69	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 9,819 bp · p 0.68 · regional, not allelic
Overall
CADD	26.0	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 0.000847% European (non-Finnish) · 10/1,179,952 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,612,992 alleles · very rare exomes 10/1,460,726 · genomes 0/152,266 · joint denominator

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.Ser564Phe
Coding: c.1691C>T
MANE Select: NM_001018115
Type: single nucleotide variant
Location: chr3:10060328 (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

Similar variants

FANCD2 p.Ser564= Likely benign ★ same residue
FANCD2 c.1279-1G>A Pathogenic/Likely pathogenic ★★ same type
FANCD2 c.1279-2A>G Likely pathogenic ★★ same type
FANCD2 c.1948-16T>G Pathogenic ★★ same type
FANCD2 c.1948-6C>A Pathogenic/Likely pathogenic ★★ same type
FANCD2 c.206-1G>T Likely pathogenic ★★ same type
FANCD2 c.2169-1G>C Likely pathogenic ★★ same type
FANCD2 c.2269+1G>A Likely pathogenic ★★ 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/fancd2-p-ser564phe (accessed [today's date]).

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