Is RTCB p.Gly252Arg (c.754G>C) pathogenic?

RTCB p.Gly252Arg (c.754G>C) is classified Uncertain significance in RTCB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely pathogenic (0.778); Very rare (popmax 0.00659%, sas).

How common is RTCB p.Gly252Arg (c.754G>C) in the general population?

RTCB p.Gly252Arg (c.754G>C) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about RTCB p.Gly252Arg (c.754G>C)?

AlphaMissense predicts likely pathogenic (score 0.778) — an in-silico prediction, not a clinical call.

RTCB p.Gly252Arg

c.754G>C · VCV3435916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.778	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -11.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 10 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00659% South Asian · 6/91,082 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00105% 17/1,614,050 alleles · very rare exomes 15/1,461,876 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,180
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)	0.000678%	147,506

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: RTCB
Protein: p.Gly252Arg
Coding: c.754G>C
MANE Select: NM_014306
Type: single nucleotide variant
Location: chr22:32398001 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 95.66 · 5 PDB

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

Similar variants

RTCB p.Gly252Glu Uncertain significance ★ ⚠ same residue
RTCB p.Ala276= Benign ★★ same type
RTCB p.Val347= Benign ★★ same type
RTCB p.Ala101Thr Uncertain significance ★ ⚠ same type
RTCB p.Ala211Val Uncertain significance ★ ⚠ same type
RTCB p.Ala242Ser Uncertain significance ★ ⚠ same type
RTCB p.Ala294Val Uncertain significance ★ ⚠ same type
RTCB p.Ala296Thr Uncertain significance ★ ⚠ 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/rtcb-p-gly252arg (accessed [today's date]).

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