Is SIX1 p.Ala54= (c.162G>A) pathogenic?

SIX1 p.Ala54= (c.162G>A) is classified Benign/Likely benign in SIX1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-12). Low-frequency (popmax 1.41%, mid); Associated with branchiootorenal syndrome 1.

What condition is associated with SIX1 p.Ala54= (c.162G>A)?

SIX1 p.Ala54= (c.162G>A) is associated with branchiootorenal syndrome 1, autosomal dominant nonsyndromic hearing loss 23, branchiootic syndrome 3 (ClinVar).

How common is SIX1 p.Ala54= (c.162G>A) in the general population?

SIX1 p.Ala54= (c.162G>A) is low-frequency (popmax 1.41%, mid) (gnomAD).

SIX1 p.Ala54=

c.162G>A · rs150550985 · VCV227075

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.41%, mid)

Conditions

branchiootorenal syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.062	GERP -1.7, phastCons 0.29
Overall
CADD	11.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.41% Middle Eastern · 85/6,046 alleles

Filtering AF 1.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.08%

Overall 0.0248% 400/1,613,950 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.41%	71
Admixed American	0.102%	984
Remaining individualsnot grpmax-eligible	0.0432%	2,315
European (non-Finnish)	0.0169%	5,930
African / African-American	0.016%	6,255
South Asian	0.0143%	7,006
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Finnishnot grpmax-eligible	0.00157%	63,842

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.Ala54=
Coding: c.162G>A
MANE Select: NM_005982
dbSNP: rs150550985
Type: single nucleotide variant
Location: chr14:60649028 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB
Residue 54: an α-helix

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

Disease context

branchiootorenal syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 23 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-ala54 (accessed [today's date]).

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