Is RHEB p.Pro2Ser (c.4C>T) pathogenic?

RHEB p.Pro2Ser (c.4C>T) is classified Uncertain significance in RHEB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-05). AlphaMissense: likely benign (0.1346); No allele count reported in gnomAD v4.1 (AN 1,554,010).

How common is RHEB p.Pro2Ser (c.4C>T) in the general population?

RHEB p.Pro2Ser (c.4C>T) is no allele count reported in gnomAD v4.1 (AN 1,554,010) (gnomAD).

What do computational predictors say about RHEB p.Pro2Ser (c.4C>T)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

RHEB p.Pro2Ser

c.4C>T · VCV3945525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,554,010)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.309	indeterminate
SaProt	LLR 1.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 4, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 52 kb · p 2.9e-22 · regional, not allelic
Overall
CADD	24.7	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

No allele count reported in gnomAD v4.1 (AN 1,554,010). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RHEB
Protein: p.Pro2Ser
Coding: c.4C>T
MANE Select: NM_005614
Type: single nucleotide variant
Location: chr7:151519508 (GRCh38)

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

Similar variants

RHEB p.Pro2Leu Uncertain significance ★ ⚠ same residue
RHEB p.Ser16Phe Uncertain significance ★★ ⚠ same type
RHEB c.333-7C>T Benign ★★ same type
RHEB p.Glu40Val Likely pathogenic ★ same type
RHEB p.Pro37Leu Pathogenic ★ same type
RHEB p.Ser68Pro Pathogenic ★ same type
RHEB p.Tyr35Asp Likely pathogenic ★ same type
RHEB p.Tyr35Cys 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/rheb-p-pro2ser (accessed [today's date]).

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