Is FANCD2 p.Gln623Pro (c.1868A>C) pathogenic?

FANCD2 p.Gln623Pro (c.1868A>C) is classified Benign/Likely benign in FANCD2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1196); Common (popmax 7.78%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with FANCD2 p.Gln623Pro (c.1868A>C)?

FANCD2 p.Gln623Pro (c.1868A>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D2 (ClinVar).

What do computational predictors say about FANCD2 p.Gln623Pro (c.1868A>C)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

FANCD2 p.Gln623Pro

Q: How common is FANCD2 p.Gln623Pro (c.1868A>C) in the general population?

FANCD2 p.Gln623Pro (c.1868A>C) is common (popmax 7.78%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1868A>C · rs36070315 · VCV134314

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.78%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -7.91	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 5.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 2,604 bp · p 5.7e-07 · regional, not allelic
Overall
CADD	24.6	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 7.78% African / African-American · 5,829/74,962 alleles

Filtering AF 7.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.54%

Overall 0.41% 6,617/1,614,084 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.78%	13
Remaining individualsnot grpmax-eligible	0.53%	189
Admixed American	0.487%	206
Middle Eastern	0.231%	433
European (non-Finnish)	0.0124%	8,082
South Asian	0.00439%	22,773
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Gln623Pro
Coding: c.1868A>C
MANE Select: NM_001018115
dbSNP: rs36070315
Type: single nucleotide variant
Location: chr3:10063832 (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 623: a UniProt-annotated variant site (in)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

FANCD2 p.Gln623Ter Pathogenic/Likely pathogenic ★★ 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
FANCD2 c.2169-1G>C Likely pathogenic ★★ same condition
FANCD2 c.2269+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-gln623pro (accessed [today's date]).

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