Is OTOF p.Ala1826Val (c.5477C>T) pathogenic?

OTOF p.Ala1826Val (c.5477C>T) is classified Conflicting classifications of pathogenicity in OTOF (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-21). AlphaMissense: ambiguous (0.4993); Ultra-rare (popmax 0.012%, afr); Associated with autosomal recessive nonsyndromic hearing loss 9.

What condition is associated with OTOF p.Ala1826Val (c.5477C>T)?

OTOF p.Ala1826Val (c.5477C>T) is associated with autosomal recessive nonsyndromic hearing loss 9 (ClinVar).

How common is OTOF p.Ala1826Val (c.5477C>T) in the general population?

OTOF p.Ala1826Val (c.5477C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about OTOF p.Ala1826Val (c.5477C>T)?

AlphaMissense predicts ambiguous (score 0.4993) — an in-silico prediction, not a clinical call.

OTOF p.Ala1826Val

c.5477C>T · rs377197565 · VCV335430

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4993 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

autosomal recessive nonsyndromic hearing loss 9

Computational evidence

Protein change
AlphaMissense	0.4993	ambiguous
REVEL	0.602	indeterminate
SaProt	LLR -6.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.81, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.00012 · regional, not allelic
Overall
CADD	28.8	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 0.012% African / African-American · 9/74,922 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000682% 11/1,614,054 alleles · ultra-rare exomes 4/1,461,874 · genomes 7/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,325
East Asian	0.00446%	22,440

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: OTOF
Protein: p.Ala1826Val
Coding: c.5477C>T
MANE Select: NM_194248
dbSNP: rs377197565
Type: single nucleotide variant
Location: chr2:26461752 (GRCh38)
Gene constraint: LOEUF 1.017 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.98
Residue 1826: the c2 7 domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OTOF p.Ala1826Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
OTOF p.Ala1826= Likely benign ★ same residue
OTOF c.2215-1G>C Likely pathogenic ★★★ same condition
OTOF c.5193-1G>A Likely pathogenic ★★★ same condition
OTOF p.Arg1583His Likely pathogenic ★★★ same condition
OTOF p.Arg1792Cys Likely pathogenic ★★★ same condition
OTOF p.Arg708Ter Pathogenic ★★★ same condition
OTOF p.Gln829Ter 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/otof-p-ala1826val (accessed [today's date]).

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