Is BRCA1 p.Ala1708Val (c.5123C>T) pathogenic?

BRCA1 p.Ala1708Val (c.5123C>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 25 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.6381); Ultra-rare (popmax 0.0294%, afr); Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Ala1708Val (c.5123C>T)?

BRCA1 p.Ala1708Val (c.5123C>T) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA1 p.Ala1708Val (c.5123C>T) in the general population?

BRCA1 p.Ala1708Val (c.5123C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about BRCA1 p.Ala1708Val (c.5123C>T)?

AlphaMissense predicts likely pathogenic (score 0.6381) — an in-silico prediction, not a clinical call.

BRCA1 p.Ala1708Val

c.5123C>T · rs28897696 · VCV37640

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 25 submitters

AlphaMissense

likely pathogenic

0.6381 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BRCA1-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.6381	likely pathogenic · top 7% in BRCA1
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	26.0	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 0.0294% African / African-American · 22/74,888 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00198% 32/1,613,780 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,404
Remaining individualsnot grpmax-eligible	0.0032%	31,239
East Asian	0.00223%	44,876
European (non-Finnish)	0.000593%	168,554

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.Ala1708Val
Coding: c.5123C>T
MANE Select: NM_007294
dbSNP: rs28897696
Type: single nucleotide variant
Location: chr17:43063903 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1708: the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; abolishes acaca binding); an α-helix

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

Disease context

Also linked: hereditary breast ovarian cancer syndrome breast cancer breast-ovarian cancer, familial, susceptibility to, 1 pancreatic cancer, susceptibility to, 4 hereditary neoplastic syndrome hereditary breast carcinoma Fanconi anemia, complementation group S

Similar variants

BRCA1 p.Ala1708Glu Pathogenic ★★★ same residue
BRCA1 p.Ala1708= Likely benign ★★★ same residue
BRCA1 p.Ala1708Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ala1708Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ala1708fs 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

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-ala1708val (accessed [today's date]).

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