Is BRCA1 p.His1686Asp (c.5056C>G) pathogenic?

BRCA1 p.His1686Asp (c.5056C>G) is classified Likely pathogenic in BRCA1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.9197); Absent from gnomAD v4.1; Associated with Fanconi anemia, complementation group S.

What condition is associated with BRCA1 p.His1686Asp (c.5056C>G)?

BRCA1 p.His1686Asp (c.5056C>G) is associated with Fanconi anemia, complementation group S, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.His1686Asp (c.5056C>G) in the general population?

BRCA1 p.His1686Asp (c.5056C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.His1686Asp (c.5056C>G)?

AlphaMissense predicts likely pathogenic (score 0.9197) — an in-silico prediction, not a clinical call.

BRCA1 p.His1686Asp

c.5056C>G · rs1555579648 · VCV867583

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9197 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia, complementation group S

Computational evidence

Protein change
AlphaMissense	0.9197	likely pathogenic ✓ concordant with ClinVar · top 3% in BRCA1
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -12.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	27.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA1
Protein: p.His1686Asp
Coding: c.5056C>G
MANE Select: NM_007294
dbSNP: rs1555579648
Type: single nucleotide variant
Location: chr17:43067626 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1686: the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; uncertain significance; functionally impaired in vitro); a β-strand

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 pancreatic cancer, susceptibility to, 4 hereditary neoplastic syndrome

Similar variants

BRCA1 p.His1686Tyr Likely pathogenic ★★★ ⚠ same residue
BRCA1 p.His1686Arg Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.His1686Gln Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.His1686= Likely benign ★★ same residue
BRCA1 p.His1686Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.His1686fs Pathogenic ★★★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T 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/brca1-p-his1686asp (accessed [today's date]).

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