Is SIX1 p.Ser72Arg (c.216C>A) pathogenic?

SIX1 p.Ser72Arg (c.216C>A) is classified Uncertain significance in SIX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-28). AlphaMissense: likely pathogenic (0.982); Very rare (popmax 0.00666%, amr); Associated with autosomal dominant nonsyndromic hearing loss 23.

What condition is associated with SIX1 p.Ser72Arg (c.216C>A)?

SIX1 p.Ser72Arg (c.216C>A) is associated with autosomal dominant nonsyndromic hearing loss 23, branchiootic syndrome 3 (ClinVar).

How common is SIX1 p.Ser72Arg (c.216C>A) in the general population?

SIX1 p.Ser72Arg (c.216C>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about SIX1 p.Ser72Arg (c.216C>A)?

AlphaMissense predicts likely pathogenic (score 0.982) — an in-silico prediction, not a clinical call.

SIX1 p.Ser72Arg

c.216C>A · rs778653697 · VCV2579593

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant nonsyndromic hearing loss 23

Computational evidence

Protein change
AlphaMissense	0.982	likely pathogenic
REVEL	0.58	indeterminate
SaProt	LLR -11.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.65, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 306 bp · p 0.92 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00666% Admixed American · 4/60,034 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000274% 4/1,461,874 alleles · very rare

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.Ser72Arg
Coding: c.216C>A
MANE Select: NM_005982
dbSNP: rs778653697
Type: single nucleotide variant
Location: chr14:60648974 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB
Residue 72: 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-ser72arg (accessed [today's date]).

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