Is SIX1 p.Pro5Gln (c.14C>A) pathogenic?

SIX1 p.Pro5Gln (c.14C>A) is classified Uncertain significance in SIX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.7232); Very rare (popmax 0.00667%, afr); Associated with branchiootic syndrome 3.

What condition is associated with SIX1 p.Pro5Gln (c.14C>A)?

SIX1 p.Pro5Gln (c.14C>A) is associated with branchiootic syndrome 3, autosomal dominant nonsyndromic hearing loss 23 (ClinVar).

How common is SIX1 p.Pro5Gln (c.14C>A) in the general population?

SIX1 p.Pro5Gln (c.14C>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about SIX1 p.Pro5Gln (c.14C>A)?

AlphaMissense predicts likely pathogenic (score 0.7232) — an in-silico prediction, not a clinical call.

SIX1 p.Pro5Gln

c.14C>A · rs771057416 · VCV2923373

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7232 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

branchiootic syndrome 3

Computational evidence

Protein change
AlphaMissense	0.7232	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -13.39	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 306 bp · p 0.92 · regional, not allelic
Overall
CADD	33.0	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 0.00667% African / African-American · 5/74,934 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000622% 10/1,608,996 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,987
Finnishnot grpmax-eligible	0.00169%	59,274
Admixed American	0.00167%	59,992
South Asian	0.0011%	91,054
European (non-Finnish)	0.00017%	589,943

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.Pro5Gln
Coding: c.14C>A
MANE Select: NM_005982
dbSNP: rs771057416
Type: single nucleotide variant
Location: chr14:60649176 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB

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

Disease context

branchiootic syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 23

Similar variants

SIX1 p.Pro5Leu Uncertain significance ★ ⚠ same residue
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

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-pro5gln (accessed [today's date]).

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