Is KRAS p.Ser65Ile (c.194G>T) pathogenic?

KRAS p.Ser65Ile (c.194G>T) is classified Likely pathogenic in KRAS (ClinVar, Expert panel, 4 submitters; last evaluated 2020-05-18). AlphaMissense: likely pathogenic (0.9398); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with KRAS p.Ser65Ile (c.194G>T)?

KRAS p.Ser65Ile (c.194G>T) is associated with RASopathy, Noonan syndrome 3 (ClinVar).

How common is KRAS p.Ser65Ile (c.194G>T) in the general population?

KRAS p.Ser65Ile (c.194G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRAS p.Ser65Ile (c.194G>T)?

AlphaMissense predicts likely pathogenic (score 0.9398) — an in-silico prediction, not a clinical call.

KRAS p.Ser65Ile

c.194G>T · rs1555194026 · VCV438796

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9398 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Likely Pathogenic for RASopathy. Applied ACMG criteria (verbatim):

PM2 PS4_Supporting PS2 PP2

Curation rationale (ClinGen, verbatim)

The c.194G>T (p.Ser65Ile) variant in KRAS was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 2 probands with clinical features of a RASopathy (PS4_Supporting; SCV000599968.1, PMID: 26822237, 25326635, Invitae internal data). The variant arose de novo in one of the probands with confirmed parentage (PS2; SCV000599968.1, PMID:26822237, 25326635). The variant is located in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581):, PS2, PS4_Supporting, PM2, PP2.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9398	likely pathogenic ✓ concordant with ClinVar
REVEL	0.6	indeterminate
SaProt	LLR -14.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 20 kb · p 1.6e-16 · regional, not allelic
Overall
CADD	28.6	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.Ser65Ile
Coding: c.194G>T
MANE Select: NM_004985 · reported on NM_033360
dbSNP: rs1555194026
Type: single nucleotide variant
Location: chr12:25227330 (GRCh38)
Gene constraint: LOEUF 0.264 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.65 · 549 PDB

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

Similar variants

KRAS p.Ser65Thr Uncertain significance ★ ⚠ 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
KRAS p.Thr58Ile Pathogenic ★★★ same condition
KRAS p.Val14Ile 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-ser65ile (accessed [today's date]).

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