Is SIX1 p.Pro81Ser (c.241C>T) pathogenic?

SIX1 p.Pro81Ser (c.241C>T) is classified Uncertain significance in SIX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.1069); Very rare (popmax 0.00127%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 23.

What condition is associated with SIX1 p.Pro81Ser (c.241C>T)?

SIX1 p.Pro81Ser (c.241C>T) is associated with autosomal dominant nonsyndromic hearing loss 23, branchiootic syndrome 3 (ClinVar).

How common is SIX1 p.Pro81Ser (c.241C>T) in the general population?

SIX1 p.Pro81Ser (c.241C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about SIX1 p.Pro81Ser (c.241C>T)?

AlphaMissense predicts likely benign (score 0.1069) — an in-silico prediction, not a clinical call.

SIX1 p.Pro81Ser

c.241C>T · VCV3761942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal dominant nonsyndromic hearing loss 23

Computational evidence

Protein change
AlphaMissense	0.1069	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -9.50	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 10	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 306 bp · p 0.92 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,180,046 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,614,210 alleles · very rare exomes 15/1,461,878 · genomes 0/152,332 · joint denominator

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: SIX1
Protein: p.Pro81Ser
Coding: c.241C>T
MANE Select: NM_005982
Type: single nucleotide variant
Location: chr14:60648949 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB
Residue 81: an α-helix

Full SIX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: branchiootic syndrome 3

Similar variants

SIX1 p.Arg110Gln Pathogenic/Likely pathogenic ★★ same condition
SIX1 p.Arg110Trp Pathogenic ★★ same condition
SIX1 p.Glu125Lys Pathogenic/Likely pathogenic ★★ same condition
SIX1 p.Tyr129Cys Pathogenic ★★ same condition
SIX1 p.Val106Met Likely pathogenic ★★ same condition
SIX1 p.Ala184Thr Uncertain significance ★★ same condition
SIX1 p.Arg119His Uncertain significance ★★ ⚠ same condition
SIX1 p.Arg140Gln 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/six1-p-pro81ser (accessed [today's date]).

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