Is NRAS p.Pro185Leu (c.554C>T) pathogenic?

NRAS p.Pro185Leu (c.554C>T) is classified Uncertain significance in NRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-20). AlphaMissense: likely benign (0.2829); Very rare (popmax 0.00119%, nfe).

How common is NRAS p.Pro185Leu (c.554C>T) in the general population?

NRAS p.Pro185Leu (c.554C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about NRAS p.Pro185Leu (c.554C>T)?

AlphaMissense predicts likely benign (score 0.2829) — an in-silico prediction, not a clinical call.

NRAS p.Pro185Leu

c.554C>T · rs2101737789 · VCV1313158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2829	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.53	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 8.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,622 bp · p 6.3e-09 · regional, not allelic
Overall
CADD	22.7	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 0.00119% European (non-Finnish) · 14/1,179,716 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00103% 15/1,461,540 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00119%	84,265
South Asian	0.0011%	91,072

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: NRAS
Protein: p.Pro185Leu
Coding: c.554C>T
MANE Select: NM_002524
dbSNP: rs2101737789
Type: single nucleotide variant
Location: chr1:114708551 (GRCh38)
Gene constraint: LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.56 · 36 PDB
Residue 185: the 'hypervariable region' region

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

Similar variants

NRAS p.Pro185Ser Uncertain significance ★★★ ⚠ same residue
NRAS p.Pro185Gln Uncertain significance ★ ⚠ same residue
NRAS p.Pro185= Likely benign ★ same residue
NRAS p.Gly12Ser Pathogenic ★★★ same type
NRAS p.Gly60Glu Pathogenic ★★★ same type
NRAS p.Ile24Asn Likely pathogenic ★★★ same type
NRAS p.Thr50Ile Pathogenic ★★★ ⚠ same type
NRAS p.Thr58Ile Pathogenic ★★★ 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/nras-p-pro185leu (accessed [today's date]).

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