Is BRCA2 p.His114Pro (c.341A>C) pathogenic?

BRCA2 p.His114Pro (c.341A>C) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-23). AlphaMissense: likely benign (0.0977); Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.His114Pro (c.341A>C)?

BRCA2 p.His114Pro (c.341A>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.His114Pro (c.341A>C) in the general population?

BRCA2 p.His114Pro (c.341A>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.His114Pro (c.341A>C)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

BRCA2 p.His114Pro

c.341A>C · rs80358586 · VCV823753

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.25	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.067	GERP -4.3, phastCons 0.001
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	10.37	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,618 alleles

Overall 6.25e-05% 1/1,600,786 alleles · very rare exomes 0/1,448,566 · genomes 1/152,220 · joint denominator

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.His114Pro
Coding: c.341A>C
MANE Select: NM_000059
dbSNP: rs80358586
Type: single nucleotide variant
Location: chr13:32325100 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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.His114Asn Uncertain significance ★★ ⚠ same residue
BRCA2 p.His114Arg Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.His114Gln Uncertain significance ★ ⚠ same residue
BRCA2 p.His114Leu Uncertain significance ★ same residue
BRCA2 p.His114Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.His114fs Pathogenic ★★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C 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-his114pro (accessed [today's date]).

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