Is BRCA1 p.Val1736Phe (c.5206G>T) pathogenic?

BRCA1 p.Val1736Phe (c.5206G>T) is classified Likely pathogenic in BRCA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.931); Very rare (popmax 6.84e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Val1736Phe (c.5206G>T)?

BRCA1 p.Val1736Phe (c.5206G>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Val1736Phe (c.5206G>T) in the general population?

BRCA1 p.Val1736Phe (c.5206G>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about BRCA1 p.Val1736Phe (c.5206G>T)?

AlphaMissense predicts likely pathogenic (score 0.931) — an in-silico prediction, not a clinical call.

BRCA1 p.Val1736Phe

c.5206G>T · rs377595653 · VCV867843

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.931	likely pathogenic ✓ concordant with ClinVar · top 2% in BRCA1
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -16.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	26.9	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 6.84e-05%

Overall 6.84e-05% 1/1,461,750 alleles · very rare

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: BRCA1
Protein: p.Val1736Phe
Coding: c.5206G>T
MANE Select: NM_007294
dbSNP: rs377595653
Type: single nucleotide variant
Location: chr17:43057123 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1736: the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc and fancs; pathogenic; decreased localization to dna damage sites and reduced interaction with uimc1/rap80)

Full BRCA1 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

BRCA1 p.Val1736Ala Pathogenic ★★★ same residue
BRCA1 p.Val1736Gly Pathogenic/Likely pathogenic ★★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+1G>A Pathogenic ★★★ same condition
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G Pathogenic ★★★ same condition
BRCA1 c.213-12A>G 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-val1736phe (accessed [today's date]).

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