Is KRAS p.Arg68Ser (c.204G>C) pathogenic?

KRAS p.Arg68Ser (c.204G>C) is classified Pathogenic/Likely pathogenic in KRAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-08). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with KRAS p.Arg68Ser (c.204G>C)?

KRAS p.Arg68Ser (c.204G>C) is associated with RASopathy, Noonan syndrome 3, cardiofaciocutaneous syndrome 2 (ClinVar).

How common is KRAS p.Arg68Ser (c.204G>C) in the general population?

KRAS p.Arg68Ser (c.204G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRAS p.Arg68Ser (c.204G>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

KRAS p.Arg68Ser

c.204G>C · VCV4698285

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic ✓ concordant with ClinVar · top 7% in KRAS
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -14.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.18, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 20 kb · p 1.6e-16 · regional, not allelic
Overall
CADD	27.2	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: KRAS
Protein: p.Arg68Ser
Coding: c.204G>C
MANE Select: NM_004985
Type: single nucleotide variant
Location: chr12:25227320 (GRCh38)
Gene constraint: LOEUF 0.264 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.65 · 549 PDB
Residue 68: an α-helix

Full KRAS 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

Also linked: Noonan syndrome 3 cardiofaciocutaneous syndrome 2

Similar variants

KRAS p.Arg68Gly Likely pathogenic ★ same residue
KRAS p.Arg68Trp Likely pathogenic ★ same residue
KRAS p.Arg68del Likely pathogenic same residue
KRAS p.Asp153Val Pathogenic ★★★ same condition
KRAS p.Gln22Arg Pathogenic ★★★ same condition
KRAS p.Gly60Arg Pathogenic ★★★ same condition
KRAS p.Lys5Asn Pathogenic ★★★ same condition
KRAS p.Pro34Leu 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/kras-p-arg68ser (accessed [today's date]).

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