Is FANCD2 p.Pro989Ala (c.2965C>G) pathogenic?

FANCD2 p.Pro989Ala (c.2965C>G) is classified Uncertain significance in FANCD2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0958); Ultra-rare (popmax 0.0662%, mid); Associated with FANCD2-related disorder.

What condition is associated with FANCD2 p.Pro989Ala (c.2965C>G)?

FANCD2 p.Pro989Ala (c.2965C>G) is associated with FANCD2-related disorder, Fanconi anemia complementation group D2, Fanconi anemia (ClinVar).

How common is FANCD2 p.Pro989Ala (c.2965C>G) in the general population?

FANCD2 p.Pro989Ala (c.2965C>G) is ultra-rare (popmax 0.0662%, mid) (gnomAD).

What do computational predictors say about FANCD2 p.Pro989Ala (c.2965C>G)?

AlphaMissense predicts likely benign (score 0.0958) — an in-silico prediction, not a clinical call.

FANCD2 p.Pro989Ala

c.2965C>G · rs200568638 · VCV134320

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0958 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0662%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FANCD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0958	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 0.67, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 36 kb · p 0.0049 · regional, not allelic
Overall
CADD	17.71	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 0.0662% Middle Eastern · 4/6,042 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0267%

Overall 0.00717% 115/1,604,526 alleles · ultra-rare exomes 108/1,452,524 · genomes 7/152,002 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0662%	1,511
South Asian	0.0407%	2,457
Admixed American	0.0183%	5,451
Remaining individualsnot grpmax-eligible	0.00965%	10,360
European (non-Finnish)	0.00461%	21,696
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,540
African / African-American	0.00268%	37,362

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.Pro989Ala
Coding: c.2965C>G
MANE Select: NM_001018115
dbSNP: rs200568638
Type: single nucleotide variant
Location: chr3:10078186 (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: Fanconi anemia complementation group D2 Fanconi anemia

Similar variants

FANCD2 p.Pro989Arg Uncertain significance ★ ⚠ same residue
FANCD2 p.Pro989= Likely benign ★ same residue
FANCD2 p.Pro989Leu Uncertain significance ★ ⚠ same residue
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

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-pro989ala (accessed [today's date]).

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