Is KRAS p.Ala66= (c.198A>G) pathogenic?

KRAS p.Ala66= (c.198A>G) is classified Benign/Likely benign in KRAS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-08). Ultra-rare (popmax 0.02%, amr); Associated with RASopathy.

What condition is associated with KRAS p.Ala66= (c.198A>G)?

KRAS p.Ala66= (c.198A>G) is associated with RASopathy (ClinVar).

How common is KRAS p.Ala66= (c.198A>G) in the general population?

KRAS p.Ala66= (c.198A>G) is ultra-rare (popmax 0.02%, amr) (gnomAD).

KRAS p.Ala66=

c.198A>G · rs200229810 · VCV45118

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP -3.8, phastCons 1
Overall
CADD	9.965	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,024 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00905% 146/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.0107%	9,364
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600

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: KRAS
Protein: p.Ala66=
Coding: c.198A>G
MANE Select: NM_004985
dbSNP: rs200229810
Type: single nucleotide variant
Location: chr12:25227326 (GRCh38)
Gene constraint: LOEUF 0.264 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.65 · 549 PDB
Residue 66: 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

Similar variants

KRAS p.Ala66Ser 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.Ser65Ile Likely pathogenic ★★★ same condition
KRAS p.Thr58Ile 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-ala66 (accessed [today's date]).

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