Is BRCA2 p.Ser2806Pro (c.8416T>C) pathogenic?

BRCA2 p.Ser2806Pro (c.8416T>C) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1121); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ser2806Pro (c.8416T>C)?

BRCA2 p.Ser2806Pro (c.8416T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Ser2806Pro (c.8416T>C) in the general population?

BRCA2 p.Ser2806Pro (c.8416T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Ser2806Pro (c.8416T>C)?

AlphaMissense predicts likely benign (score 0.1121) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser2806Pro

c.8416T>C · rs1280487930 · VCV807003

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1121	likely benign
REVEL	0.449	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.2	GERP 0.79, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,054 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,858 alleles · very rare exomes 6/1,461,498 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,054
European (non-Finnish)	0.000424%	235,940

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: BRCA2
Protein: p.Ser2806Pro
Coding: c.8416T>C
MANE Select: NM_000059
dbSNP: rs1280487930
Type: single nucleotide variant
Location: chr13:32370486 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2806: the 'interaction with sem1' region

Full BRCA2 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

Similar variants

BRCA2 p.Ser2806Ter Pathogenic ★★ same residue
BRCA2 p.Ser2806Leu Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser2806= Likely benign ★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C Pathogenic ★★★ same condition
BRCA2 c.475+1G>A 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/brca2-p-ser2806pro (accessed [today's date]).

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