Is RAF1 p.Arg554Ter (c.1660C>T) pathogenic?

RAF1 p.Arg554Ter (c.1660C>T) is classified Uncertain significance in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-19). Very rare (popmax 0.0011%, sas); Associated with RASopathy.

What condition is associated with RAF1 p.Arg554Ter (c.1660C>T)?

RAF1 p.Arg554Ter (c.1660C>T) is associated with RASopathy (ClinVar).

How common is RAF1 p.Arg554Ter (c.1660C>T) in the general population?

RAF1 p.Arg554Ter (c.1660C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

RAF1 p.Arg554Ter

c.1660C>T · rs925151637 · VCV1044030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 15 of 17
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 0.73, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Overall 0.000657% 1/152,110 alleles · very rare

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: RAF1
Protein: p.Arg554Ter
Coding: c.1660C>T
MANE Select: NM_002880
dbSNP: rs925151637
Type: single nucleotide variant
Location: chr3:12585130 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 554: an α-helix; the protein kinase domain

Full RAF1 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

RAF1 p.Arg554Gln Uncertain significance ★★ ⚠ same residue
RAF1 p.Arg554= Likely benign ★★ same residue
RAF1 p.Arg554Gly Uncertain significance ★ ⚠ same residue
RAF1 p.Arg256Ser Likely pathogenic ★★★ ⚠ same condition
RAF1 p.Gly361Ala Pathogenic ★★★ ⚠ same condition
RAF1 p.Leu613Val Pathogenic ★★★ same condition
RAF1 p.Pro261Ser Pathogenic ★★★ ⚠ same condition
RAF1 p.Ser257Leu 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/raf1-p-arg554ter (accessed [today's date]).

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