Is BRCA1 p.Val415Ile (c.1243G>A) pathogenic?

BRCA1 p.Val415Ile (c.1243G>A) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.085); Ultra-rare (popmax 0.0183%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Val415Ile (c.1243G>A)?

BRCA1 p.Val415Ile (c.1243G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Val415Ile (c.1243G>A) in the general population?

BRCA1 p.Val415Ile (c.1243G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about BRCA1 p.Val415Ile (c.1243G>A)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

BRCA1 p.Val415Ile

c.1243G>A · rs587782770 · VCV142855

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.74	GERP -4.8
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	7.607	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 0.0183% Admixed American · 11/59,996 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00254% 41/1,614,036 alleles · ultra-rare exomes 33/1,461,850 · genomes 8/152,186 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0344%	2,910
Admixed Americangrpmax	0.0183%	5,454
East Asian	0.00891%	11,223
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	590,019

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val415Ile
Coding: c.1243G>A
MANE Select: NM_007294
dbSNP: rs587782770
Type: single nucleotide variant
Location: chr17:43094288 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB

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 breast-ovarian cancer, familial, susceptibility to, 1

Similar variants

BRCA1 p.Val415Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Val415Leu Uncertain significance ★ ⚠ same residue
BRCA1 p.Val415Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Val415= Likely benign ★ 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-val415ile (accessed [today's date]).

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