Is RTCB p.Leu126Phe (c.378G>C) pathogenic?

RTCB p.Leu126Phe (c.378G>C) is classified Uncertain significance in RTCB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-15). AlphaMissense: likely pathogenic (0.8708); Very rare (popmax 8.47e-05%, nfe).

How common is RTCB p.Leu126Phe (c.378G>C) in the general population?

RTCB p.Leu126Phe (c.378G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about RTCB p.Leu126Phe (c.378G>C)?

AlphaMissense predicts likely pathogenic (score 0.8708) — an in-silico prediction, not a clinical call.

RTCB p.Leu126Phe

c.378G>C · rs753967453 · VCV2335179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8708	likely pathogenic
REVEL	0.348	indeterminate
SaProt	LLR -11.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.82	GERP 0.66, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 10 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	23.6	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 8.47e-05% European (non-Finnish) · 1/1,179,978 alleles

Overall 6.2e-05% 1/1,614,098 alleles · very rare exomes 1/1,461,798 · genomes 0/152,300 · joint denominator

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.Leu126Phe
Coding: c.378G>C
MANE Select: NM_014306
dbSNP: rs753967453
Type: single nucleotide variant
Location: chr22:32401866 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 95.66 · 5 PDB
Residue 126: a β-strand

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

Similar variants

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
RTCB p.Ala333Ser 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-leu126phe (accessed [today's date]).

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