Is SIX3 p.Ala72= (c.216C>T) pathogenic?

SIX3 p.Ala72= (c.216C>T) is classified Likely benign in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). Very rare (popmax 0.00168%, amr); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Ala72= (c.216C>T)?

SIX3 p.Ala72= (c.216C>T) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Ala72= (c.216C>T) in the general population?

SIX3 p.Ala72= (c.216C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

SIX3 p.Ala72=

c.216C>T · rs746201264 · VCV708058

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Conditions

holoprosencephaly 2

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 3.7	GERP -3.1, phastCons 1
Overall
CADD	15.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,460 alleles

Overall 0.000126% 2/1,590,538 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,460
European (non-Finnish)	8.5e-05%	1,175,996

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: SIX3
Protein: p.Ala72=
Coding: c.216C>T
MANE Select: NM_005413
dbSNP: rs746201264
Type: single nucleotide variant
Location: chr2:44942320 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 72: the 'interaction with tle5' region

Full SIX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

holoprosencephaly 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same residue
SIX3 p.Ala72Ser Uncertain significance ★ ⚠ same residue
SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg201His Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg281Ser Uncertain significance ★★ same condition
SIX3 p.Asp205His Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly244Cys 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/six3-p-ala72 (accessed [today's date]).

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