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

TECTA p.Arg474Cys (c.1420C>T) is classified Uncertain significance in TECTA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-02). AlphaMissense: likely pathogenic (0.7014); Ultra-rare (popmax 0.0164%, mid); Associated with autosomal recessive nonsyndromic hearing loss 21.

What condition is associated with TECTA p.Arg474Cys (c.1420C>T)?

TECTA p.Arg474Cys (c.1420C>T) is associated with autosomal recessive nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 12 (ClinVar).

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

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

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

AlphaMissense predicts likely pathogenic (score 0.7014) — an in-silico prediction, not a clinical call.

TECTA p.Arg474Cys

c.1420C>T · rs756326790 · VCV302999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7014 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 21

Computational evidence

Protein change
AlphaMissense	0.7014	likely pathogenic
REVEL	0.261	benign-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 66 kb · p 0.00019 · regional, not allelic
Overall
CADD	31.0	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 · 1/6,084 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00211% 34/1,614,064 alleles · ultra-rare exomes 30/1,461,836 · genomes 4/152,228 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00445%	22,451
African / African-American	0.004%	24,980
European (non-Finnish)	0.0022%	45,386
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,092

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: TECTA
Protein: p.Arg474Cys
Coding: c.1420C>T
MANE Select: NM_005422
dbSNP: rs756326790
Type: single nucleotide variant
Location: chr11:121125518 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.64
Residue 474: the vwfd 1 domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 21 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 12

Similar variants

TECTA p.Arg371Gly Benign ★★★ same condition
TECTA c.2367+2T>C Likely pathogenic ★★ same condition
TECTA c.4690-1G>A Pathogenic/Likely pathogenic ★★ same condition
TECTA p.Arg1174Ter Pathogenic ★★ same condition
TECTA p.Ala567Thr Uncertain significance ★★ ⚠ same condition
TECTA p.Arg284Cys Uncertain significance ★★ ⚠ same condition
TECTA p.Cys1072= Uncertain significance ★★ same condition
TECTA p.Cys1402Ser Uncertain significance ★★ ⚠ same condition

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/tecta-p-arg474cys (accessed [today's date]).

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