Is BRD8 p.Ser66Phe (c.197C>T) pathogenic?

BRD8 p.Ser66Phe (c.197C>T) is classified Uncertain significance in BRD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.9682); Very rare (popmax 0.00146%, nfe).

How common is BRD8 p.Ser66Phe (c.197C>T) in the general population?

BRD8 p.Ser66Phe (c.197C>T) is very rare (popmax 0.00146%, nfe) (gnomAD).

What do computational predictors say about BRD8 p.Ser66Phe (c.197C>T)?

AlphaMissense predicts likely pathogenic (score 0.9682) — an in-silico prediction, not a clinical call.

BRD8 p.Ser66Phe

c.197C>T · VCV3992989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00146%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9682	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 7,515 bp · p 1.8e-06 · regional, not allelic
Overall
CADD	32.0	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 0.00146% European (non-Finnish) · 17/1,168,144 alleles

Filtering AF 0.000886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000725%

Overall 0.00108% 17/1,580,438 alleles · very rare exomes 15/1,450,186 · genomes 2/130,252 · joint denominator

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: BRD8
Protein: p.Ser66Phe
Coding: c.197C>T
MANE Select: NM_139199
Type: single nucleotide variant
Location: chr5:138171400 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.92

Full BRD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRD8 p.Ala165Val Uncertain significance ★ ⚠ same type
BRD8 p.Ala211Thr Uncertain significance ★ ⚠ same type
BRD8 p.Ala264Val Uncertain significance ★ ⚠ same type
BRD8 p.Ala273Ser Uncertain significance ★ ⚠ same type
BRD8 p.Ala314Val Uncertain significance ★ ⚠ same type
BRD8 p.Ala331Thr Uncertain significance ★ ⚠ same type
BRD8 p.Ala437Thr Uncertain significance ★ ⚠ same type
BRD8 p.Ala553Val Uncertain significance ★ ⚠ same type

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/brd8-p-ser66phe (accessed [today's date]).

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