Is STRC p.Arg1391Cys (c.4171C>T) pathogenic?

STRC p.Arg1391Cys (c.4171C>T) is classified Conflicting classifications of pathogenicity in STRC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-09). AlphaMissense: likely benign (0.2569); Very rare (popmax 0.00903%, eas); Associated with autosomal recessive nonsyndromic hearing loss 16.

What condition is associated with STRC p.Arg1391Cys (c.4171C>T)?

STRC p.Arg1391Cys (c.4171C>T) is associated with autosomal recessive nonsyndromic hearing loss 16 (ClinVar).

How common is STRC p.Arg1391Cys (c.4171C>T) in the general population?

STRC p.Arg1391Cys (c.4171C>T) is very rare (popmax 0.00903%, eas) (gnomAD).

What do computational predictors say about STRC p.Arg1391Cys (c.4171C>T)?

AlphaMissense predicts likely benign (score 0.2569) — an in-silico prediction, not a clinical call.

STRC p.Arg1391Cys

c.4171C>T · rs376104748 · VCV517451

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00903%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive nonsyndromic hearing loss 16

Computational evidence

Protein change
AlphaMissense	0.2569	likely benign
REVEL	0.643	indeterminate
SaProt	LLR -5.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.062, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,913 bp · p 0.26 · regional, not allelic
Overall
CADD	26.4	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 0.00903% East Asian · 4/44,314 alleles

Filtering AF 0.003% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00182%

Overall 0.00158% 25/1,587,164 alleles · very rare exomes 23/1,435,348 · genomes 2/151,816 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00903%	11,079
Admixed American	0.00529%	18,906
South Asian	0.00452%	22,133
European (non-Finnish)	0.0012%	83,103

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.Arg1391Cys
Coding: c.4171C>T
MANE Select: NM_153700
dbSNP: rs376104748
Type: single nucleotide variant
Location: chr15:43604408 (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

autosomal recessive nonsyndromic hearing loss 16 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STRC p.Arg1391Gly Conflicting classifications of pathogenicity ★ same residue
STRC c.4219-1G>A Pathogenic/Likely pathogenic ★★ same condition
STRC c.4701+1G>A Pathogenic/Likely pathogenic ★★ same condition
STRC p.Arg1073Ter Pathogenic ★★ same condition
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

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-arg1391cys (accessed [today's date]).

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