Is FANCD2 p.Pro1289Ser (c.3865C>T) pathogenic?

FANCD2 p.Pro1289Ser (c.3865C>T) is classified Uncertain significance in FANCD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). AlphaMissense: likely benign (0.1271); Very rare (popmax 0.000763%, nfe); Associated with Fanconi anemia complementation group D2.

What condition is associated with FANCD2 p.Pro1289Ser (c.3865C>T)?

FANCD2 p.Pro1289Ser (c.3865C>T) is associated with Fanconi anemia complementation group D2 (ClinVar).

How common is FANCD2 p.Pro1289Ser (c.3865C>T) in the general population?

FANCD2 p.Pro1289Ser (c.3865C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about FANCD2 p.Pro1289Ser (c.3865C>T)?

AlphaMissense predicts likely benign (score 0.1271) — an in-silico prediction, not a clinical call.

FANCD2 p.Pro1289Ser

c.3865C>T · rs781605384 · VCV1327072

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Fanconi anemia complementation group D2

Computational evidence

Protein change
AlphaMissense	0.1271	likely benign
REVEL	0.415	indeterminate
SaProt	LLR -5.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.45	donor loss, 23 bp away · masked 0 · deltas
Pangolin	Δ0.42	loss · gain 0.31 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 36 kb · p 0.0049 · regional, not allelic
Overall
CADD	25.4	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 0.000763% European (non-Finnish) · 9/1,179,472 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,256 alleles · very rare

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.Pro1289Ser
Coding: c.3865C>T
MANE Select: NM_001018115
dbSNP: rs781605384
Type: single nucleotide variant
Location: chr3:10093300 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.24 · 13 PDB
Residue 1289: an α-helix

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

Disease context

Fanconi anemia complementation group D2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-pro1289ser (accessed [today's date]).

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