Is STRC p.Trp1475Cys (c.4425G>C) pathogenic?

STRC p.Trp1475Cys (c.4425G>C) is classified Pathogenic/Likely pathogenic in STRC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-09). AlphaMissense: likely pathogenic (0.9901); Very rare (popmax 0.00237%, nfe); Associated with STRC-related disorder.

What condition is associated with STRC p.Trp1475Cys (c.4425G>C)?

STRC p.Trp1475Cys (c.4425G>C) is associated with STRC-related disorder, autosomal recessive nonsyndromic hearing loss 16 (ClinVar).

How common is STRC p.Trp1475Cys (c.4425G>C) in the general population?

STRC p.Trp1475Cys (c.4425G>C) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about STRC p.Trp1475Cys (c.4425G>C)?

AlphaMissense predicts likely pathogenic (score 0.9901) — an in-silico prediction, not a clinical call.

STRC p.Trp1475Cys

c.4425G>C · rs727503443 · VCV165308

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

STRC-related disorder

Computational evidence

Protein change
AlphaMissense	0.9901	likely pathogenic ✓ concordant with ClinVar · top 1% in STRC
REVEL	0.74	pathogenic-leaning
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -0.38, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,913 bp · p 0.26 · regional, not allelic
Overall
CADD	26.8	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 0.00237% European (non-Finnish) · 28/1,179,872 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00186% 30/1,613,668 alleles · very rare exomes 28/1,461,656 · genomes 2/152,012 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,138
Admixed American	0.00167%	59,980
African / African-American	0.00134%	74,848

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: STRC
Protein: p.Trp1475Cys
Coding: c.4425G>C
MANE Select: NM_153700
dbSNP: rs727503443
Type: single nucleotide variant
Location: chr15:43603362 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.21

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

Disease context

STRC-related disorder

Also linked: autosomal recessive nonsyndromic hearing loss 16

Similar variants

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STRC p.Arg1154Ter Pathogenic/Likely pathogenic ★★ same condition
STRC p.Arg1224Ter Pathogenic ★★ same condition
STRC p.Arg1338Ter Pathogenic/Likely pathogenic ★★ same condition
STRC p.Arg1451Ter Pathogenic/Likely pathogenic ★★ same condition
STRC p.Arg1468Ter Pathogenic ★★ 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/strc-p-trp1475cys (accessed [today's date]).

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