Is BRIP1 p.Ala185Thr (c.553G>A) pathogenic?

BRIP1 p.Ala185Thr (c.553G>A) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0624); Ultra-rare (popmax 0.0791%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Ala185Thr (c.553G>A)?

BRIP1 p.Ala185Thr (c.553G>A) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Ala185Thr (c.553G>A) in the general population?

BRIP1 p.Ala185Thr (c.553G>A) is ultra-rare (popmax 0.0791%, sas) (gnomAD).

What do computational predictors say about BRIP1 p.Ala185Thr (c.553G>A)?

AlphaMissense predicts likely benign (score 0.0624) — an in-silico prediction, not a clinical call.

BRIP1 p.Ala185Thr

c.553G>A · rs745645356 · VCV407849

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0624 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0791%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0624	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -3.2
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	2.206	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 0.0791% South Asian · 72/91,072 alleles

Filtering AF 0.0643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00452% 73/1,613,386 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0791%	1,265
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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: BRIP1
Protein: p.Ala185Thr
Coding: c.553G>A
MANE Select: NM_032043
dbSNP: rs745645356
Type: single nucleotide variant
Location: chr17:61847175 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 185: the helicase atp-binding domain; a binding site

Full BRIP1 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: Fanconi anemia complementation group J hereditary breast carcinoma

Similar variants

BRIP1 p.Ala185Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Ala185= Likely benign ★ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>C Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>G Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>T Likely pathogenic ★★ same condition
BRIP1 c.1340+1G>A Pathogenic/Likely pathogenic ★★ same condition
BRIP1 c.1341-1G>A Likely 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/brip1-p-ala185thr (accessed [today's date]).

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