Is THBD p.Arg474Cys (c.1420C>T) pathogenic?

THBD p.Arg474Cys (c.1420C>T) is classified Uncertain significance in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: ambiguous (0.3916); Ultra-rare (popmax 0.0164%, mid).

How common is THBD p.Arg474Cys (c.1420C>T) in the general population?

THBD p.Arg474Cys (c.1420C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about THBD p.Arg474Cys (c.1420C>T)?

AlphaMissense predicts ambiguous (score 0.3916) — an in-silico prediction, not a clinical call.

THBD p.Arg474Cys

c.1420C>T · rs766214166 · VCV2084147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3916 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3916	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -8.63	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.61	GERP -0.73, phastCons 0.15
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	19.01	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00577% 93/1,612,356 alleles · ultra-rare exomes 90/1,460,108 · genomes 3/152,248 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.00771%	12,963
African / African-American	0.00133%	74,940

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: THBD
Protein: p.Arg474Cys
Coding: c.1420C>T
MANE Select: NM_000361
dbSNP: rs766214166
Type: single nucleotide variant
Location: chr20:23048085 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 474: the egf-like 6; calcium-binding domain; a β-strand

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

Similar variants

THBD p.Arg474Gly Uncertain significance ★ ⚠ same residue
THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same type
THBD p.Ala139Ser Uncertain significance ★★ ⚠ same type
THBD p.Ala21Ser Uncertain significance ★★ ⚠ same type
THBD p.Ala255Pro Uncertain significance ★★ ⚠ same type
THBD p.Ala271Thr Uncertain significance ★★ ⚠ same type
THBD p.Ala272Val Uncertain significance ★★ ⚠ same type
THBD p.Ala284Gly 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/thbd-p-arg474cys (accessed [today's date]).

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