Is FANCD2 p.Pro593Ser (c.1777C>T) pathogenic?

FANCD2 p.Pro593Ser (c.1777C>T) is classified Conflicting classifications of pathogenicity in FANCD2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0581); Rare (popmax 0.332%, mid); Associated with FANCD2-related disorder.

What condition is associated with FANCD2 p.Pro593Ser (c.1777C>T)?

FANCD2 p.Pro593Ser (c.1777C>T) is associated with FANCD2-related disorder, breast cancer, Fanconi anemia complementation group D2 (ClinVar).

How common is FANCD2 p.Pro593Ser (c.1777C>T) in the general population?

FANCD2 p.Pro593Ser (c.1777C>T) is rare (popmax 0.332%, mid) (gnomAD).

What do computational predictors say about FANCD2 p.Pro593Ser (c.1777C>T)?

AlphaMissense predicts likely benign (score 0.0581) — an in-silico prediction, not a clinical call.

FANCD2 p.Pro593Ser

c.1777C>T · rs147523071 · VCV134313

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0581 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.332%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FANCD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0581	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -4.21	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 1.2	GERP -1.1, phastCons 0.004
Regional constraint	o/e 0.96	unconstrained · MANE · 9,819 bp · p 0.68 · regional, not allelic
Overall
CADD	0.228	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 0.332% Middle Eastern · 20/6,018 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.184%

Overall 0.108% 1,738/1,611,616 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.332%	301
European (non-Finnish)	0.13%	771
Remaining individualsnot grpmax-eligible	0.119%	844
Admixed American	0.0718%	1,394
South Asian	0.0465%	2,153
African / African-American	0.0294%	3,405
Finnishnot grpmax-eligible	0.0141%	7,097

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.Pro593Ser
Coding: c.1777C>T
MANE Select: NM_001018115
dbSNP: rs147523071
Type: single nucleotide variant
Location: chr3:10062161 (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

FANCD2-related disorder

Also linked: breast cancer Fanconi anemia complementation group D2 hereditary neoplastic syndrome Fanconi anemia

Similar variants

FANCD2 c.1279-1G>A Pathogenic/Likely pathogenic ★★ same condition
FANCD2 c.1279-2A>G Likely pathogenic ★★ same condition
FANCD2 c.1948-16T>G Pathogenic ★★ same condition
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

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-pro593ser (accessed [today's date]).

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