Is BRCA1 p.Ala1623Val (c.4868C>T) pathogenic?

BRCA1 p.Ala1623Val (c.4868C>T) is classified Uncertain significance in BRCA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-20). AlphaMissense: likely benign (0.1018); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Ala1623Val (c.4868C>T)?

BRCA1 p.Ala1623Val (c.4868C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Ala1623Val (c.4868C>T) in the general population?

BRCA1 p.Ala1623Val (c.4868C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Ala1623Val (c.4868C>T)?

AlphaMissense predicts likely benign (score 0.1018) — an in-silico prediction, not a clinical call.

BRCA1 p.Ala1623Val

c.4868C>T · rs80356862 · VCV1325655

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1018 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1018	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.92 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2	GERP -0.51, phastCons 0.023
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	4.983	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 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.Ala1623Val
Coding: c.4868C>T
MANE Select: NM_007294
dbSNP: rs80356862
Type: single nucleotide variant
Location: chr17:43071046 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1623: a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in brovca1; major splicing aberration identified with this mutant)

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.Ala1623Gly Pathogenic/Likely pathogenic ★★ ⚠ same residue
BRCA1 p.Ala1623Thr Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ala1623= Likely benign ★★ same residue
BRCA1 p.Ala1623Ser 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
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-ala1623val (accessed [today's date]).

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