Is BRCA1 p.Leu1404Arg (c.4211T>G) pathogenic?

BRCA1 p.Leu1404Arg (c.4211T>G) is classified Uncertain significance in BRCA1 (ClinVar, Expert panel, 9 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.5861); Absent from gnomAD v4.1; Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Leu1404Arg (c.4211T>G)?

BRCA1 p.Leu1404Arg (c.4211T>G) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, ovarian cancer (ClinVar).

How common is BRCA1 p.Leu1404Arg (c.4211T>G) in the general population?

BRCA1 p.Leu1404Arg (c.4211T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Leu1404Arg (c.4211T>G)?

AlphaMissense predicts likely pathogenic (score 0.5861) — an in-silico prediction, not a clinical call.

BRCA1 p.Leu1404Arg

c.4211T>G · rs80356916 · VCV491071

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.5861 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

BRCA1-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.5861	likely pathogenic · top 8% in BRCA1
REVEL	0.331	indeterminate
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.5	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.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Uncertain Significance for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

PM2_Supporting PP1 BP4

Curation rationale (ClinGen, verbatim)

The c.4211T>G variant in BRCA1 is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 1404 (p.(Leu1404Arg)). This variant is absent from gnomAD v4.1 (read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.09, which is below the recommended threshold of 0.15 for predicting no impact on BRCA1 via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (BP4 met). Cosegregation analysis of one family carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 3.9 (applied as LR), within the thresholds for supporting pathogenic evidence (LR ≥2.08 & <4.3) (PP1 met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP4, PM2_Supporting, PP1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA1
Protein: p.Leu1404Arg
Coding: c.4211T>G
MANE Select: NM_007294
dbSNP: rs80356916
Type: single nucleotide variant
Location: chr17:43082550 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1404: the 'interaction with palb2' region; a UniProt-annotated variant site (in fancs)

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

Disease context

Also linked: hereditary breast ovarian cancer syndrome ovarian cancer breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome hereditary breast carcinoma Fanconi anemia, complementation group S

Similar variants

BRCA1 p.Leu1404Pro Uncertain significance ★★ ⚠ same residue
BRCA1 p.Leu1404Met Uncertain significance ★ same residue
BRCA1 p.Leu1404= Likely benign ★ same residue
BRCA1 p.Leu1404fs 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

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-leu1404arg (accessed [today's date]).

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