Is RTCB p.Asn205Ser (c.614A>G) pathogenic?

RTCB p.Asn205Ser (c.614A>G) is classified Uncertain significance in RTCB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: likely benign (0.045); Very rare (popmax 0.00329%, sas).

How common is RTCB p.Asn205Ser (c.614A>G) in the general population?

RTCB p.Asn205Ser (c.614A>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about RTCB p.Asn205Ser (c.614A>G)?

AlphaMissense predicts likely benign (score 0.045) — an in-silico prediction, not a clinical call.

RTCB p.Asn205Ser

c.614A>G · VCV4580038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.045	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -4.03	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 4.2	GERP 0.73, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 10 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	11.39	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 0.00329% South Asian · 3/91,052 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00031% 5/1,613,946 alleles · very rare exomes 4/1,461,730 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,351
East Asian	0.00223%	44,876
Admixed American	0.00167%	60,016

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.Asn205Ser
Coding: c.614A>G
MANE Select: NM_014306
Type: single nucleotide variant
Location: chr22:32399643 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 95.66 · 5 PDB
Residue 205: 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-asn205ser (accessed [today's date]).

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