Is BRAF p.Ala621Ser (c.1861G>T) pathogenic?

BRAF p.Ala621Ser (c.1861G>T) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-06). AlphaMissense: ambiguous (0.3691); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with BRAF p.Ala621Ser (c.1861G>T)?

BRAF p.Ala621Ser (c.1861G>T) is associated with RASopathy (ClinVar).

How common is BRAF p.Ala621Ser (c.1861G>T) in the general population?

BRAF p.Ala621Ser (c.1861G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRAF p.Ala621Ser (c.1861G>T)?

AlphaMissense predicts ambiguous (score 0.3691) — an in-silico prediction, not a clinical call.

BRAF p.Ala621Ser

c.1861G>T · rs2128994651 · VCV1405108

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3691 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3691	ambiguous
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -11.53	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 4, phastCons 1
Overall
CADD	33.0	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

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: BRAF
Protein: p.Ala621Ser
Coding: c.1861G>T
MANE Select: NM_004333
dbSNP: rs2128994651
Type: single nucleotide variant
Location: chr7:140749418 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 621: the protein kinase domain

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

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRAF p.Ala246Pro Pathogenic ★★★ same condition
BRAF p.Asn581Asp Pathogenic ★★★ same condition
BRAF p.Asp594Val Pathogenic ★★★ same condition
BRAF p.Cys532Tyr Likely pathogenic ★★★ same condition
BRAF p.Gln257Arg Pathogenic ★★★ same condition
BRAF p.Gly265Arg Likely pathogenic ★★★ same condition
BRAF p.Gly464Glu Pathogenic ★★★ same condition
BRAF p.Gly469Glu 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/braf-p-ala621ser (accessed [today's date]).

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