Is BRCA1 p.Glu1346Lys (c.4036G>A) pathogenic?

BRCA1 p.Glu1346Lys (c.4036G>A) is classified Benign/Likely benign in BRCA1 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1053); Very rare (popmax 0.00568%, nfe); Associated with Fanconi anemia, complementation group S.

What condition is associated with BRCA1 p.Glu1346Lys (c.4036G>A)?

BRCA1 p.Glu1346Lys (c.4036G>A) 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.Glu1346Lys (c.4036G>A) in the general population?

BRCA1 p.Glu1346Lys (c.4036G>A) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Glu1346Lys (c.4036G>A)?

AlphaMissense predicts likely benign (score 0.1053) — an in-silico prediction, not a clinical call.

BRCA1 p.Glu1346Lys

c.4036G>A · rs80357407 · VCV37561

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely benign

0.1053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Fanconi anemia, complementation group S

Computational evidence

Protein change
AlphaMissense	0.1053	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.19, phastCons 0.94
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	17.05	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 0.00568% European (non-Finnish) · 67/1,179,598 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00428% 69/1,613,396 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,606
Remaining individualsnot grpmax-eligible	0.0032%	31,229

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.Glu1346Lys
Coding: c.4036G>A
MANE Select: NM_007294
dbSNP: rs80357407
Type: single nucleotide variant
Location: chr17:43091495 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1346: a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; uncertain significance; functionally neutral in vitro); the 'disordered' region

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 hereditary neoplastic syndrome BRCA1-related cancer predisposition

Similar variants

BRCA1 p.Glu1346Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Glu1346Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Glu1346= Likely benign ★ same residue
BRCA1 p.Glu1346fs Pathogenic ★★★ same residue
BRCA1 p.Glu1346del Uncertain significance ★★ 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

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-glu1346lys (accessed [today's date]).

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