Is RTCB p.Val136Ile (c.406G>A) pathogenic?

RTCB p.Val136Ile (c.406G>A) is classified Uncertain significance in RTCB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely benign (0.1044); Ultra-rare (popmax 0.0834%, sas).

How common is RTCB p.Val136Ile (c.406G>A) in the general population?

RTCB p.Val136Ile (c.406G>A) is ultra-rare (popmax 0.0834%, sas) (gnomAD).

What do computational predictors say about RTCB p.Val136Ile (c.406G>A)?

AlphaMissense predicts likely benign (score 0.1044) — an in-silico prediction, not a clinical call.

RTCB p.Val136Ile

c.406G>A · VCV3435913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1044 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0834%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1044	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -8.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 10 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	22.9	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 0.0834% South Asian · 76/91,076 alleles

Filtering AF 0.0683% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0628%

Overall 0.00489% 79/1,614,110 alleles · ultra-rare exomes 72/1,461,792 · genomes 7/152,318 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0834%	1,198
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)	8.47e-05%	1,179,967

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.Val136Ile
Coding: c.406G>A
MANE Select: NM_014306
Type: single nucleotide variant
Location: chr22:32401838 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 95.66 · 5 PDB
Residue 136: an α-helix

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-val136ile (accessed [today's date]).

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