Is RRAS p.Pro214Ser (c.640C>T) pathogenic?

RRAS p.Pro214Ser (c.640C>T) is classified Uncertain significance in RRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-20). AlphaMissense: likely benign (0.1153); Ultra-rare (popmax 0.0125%, eas).

How common is RRAS p.Pro214Ser (c.640C>T) in the general population?

RRAS p.Pro214Ser (c.640C>T) is ultra-rare (popmax 0.0125%, eas) (gnomAD).

What do computational predictors say about RRAS p.Pro214Ser (c.640C>T)?

AlphaMissense predicts likely benign (score 0.1153) — an in-silico prediction, not a clinical call.

RRAS p.Pro214Ser

c.640C>T · VCV3435499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1153 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1153	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -3.36	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,519 bp · p 0.14 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% East Asian · 5/39,946 alleles

Filtering AF 0.00488% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00315%

Overall 0.000346% 5/1,446,766 alleles · ultra-rare exomes 5/1,294,636 · genomes 0/152,130 · 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: RRAS
Protein: p.Pro214Ser
Coding: c.640C>T
MANE Select: NM_006270
Type: single nucleotide variant
Location: chr19:49635593 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.79 · 2 PDB

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

Similar variants

RRAS p.Pro214= Likely benign ★★ same residue
RRAS p.Ala109Thr Uncertain significance ★★ ⚠ same type
RRAS p.Ala162Thr Uncertain significance ★★ ⚠ same type
RRAS p.Ala205Val Uncertain significance ★★ ⚠ same type
RRAS p.Ala85Val Uncertain significance ★★ ⚠ same type
RRAS p.Arg113Gln Uncertain significance ★★ ⚠ same type
RRAS p.Arg128Gln Uncertain significance ★★ ⚠ same type
RRAS p.Arg132Cys 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/rras-p-pro214ser (accessed [today's date]).

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