Is SLC26A4 p.His135Pro (c.404A>C) pathogenic?

SLC26A4 p.His135Pro (c.404A>C) is classified Likely pathogenic in SLC26A4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.9666); Absent from gnomAD v4.1; Associated with autosomal recessive nonsyndromic hearing loss 4.

What condition is associated with SLC26A4 p.His135Pro (c.404A>C)?

SLC26A4 p.His135Pro (c.404A>C) is associated with autosomal recessive nonsyndromic hearing loss 4 (ClinVar).

How common is SLC26A4 p.His135Pro (c.404A>C) in the general population?

SLC26A4 p.His135Pro (c.404A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SLC26A4 p.His135Pro (c.404A>C)?

AlphaMissense predicts likely pathogenic (score 0.9666) — an in-silico prediction, not a clinical call.

SLC26A4 p.His135Pro

c.404A>C · VCV3601774

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9666 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 4

Computational evidence

Protein change
AlphaMissense	0.9666	likely pathogenic ✓ concordant with ClinVar · top 6% in SLC26A4
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -12.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 54 kb · p 4.2e-09 · regional, not allelic
Overall
CADD	27.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SLC26A4
Protein: p.His135Pro
Coding: c.404A>C
MANE Select: NM_000441
Type: single nucleotide variant
Location: chr7:107672237 (GRCh38)
Gene constraint: LOEUF 1.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.72

Full SLC26A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC26A4 c.919-2A>G Pathogenic ★★★ same condition
SLC26A4 p.Arg185Thr Likely pathogenic ★★★ same condition
SLC26A4 p.Cys282Tyr Likely pathogenic ★★★ same condition
SLC26A4 p.Cys565Tyr Likely pathogenic ★★★ ⚠ same condition
SLC26A4 p.Ile655Val Likely pathogenic ★★★ ⚠ same condition
SLC26A4 p.Leu117Phe Pathogenic ★★★ same condition
SLC26A4 p.Leu236Val Pathogenic ★★★ ⚠ same condition
SLC26A4 p.Phe335Leu 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/slc26a4-p-his135pro (accessed [today's date]).

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