Is SIX3 p.Pro116= (c.348C>T) pathogenic?

SIX3 p.Pro116= (c.348C>T) is classified Benign/Likely benign in SIX3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). Rare (popmax 0.153%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Pro116= (c.348C>T)?

SIX3 p.Pro116= (c.348C>T) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Pro116= (c.348C>T) in the general population?

SIX3 p.Pro116= (c.348C>T) is rare (popmax 0.153%, nfe) (gnomAD).

SIX3 p.Pro116=

c.348C>T · rs573768953 · VCV586592

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.153%, nfe)

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 0.58	GERP -4.2, phastCons 1
Overall
CADD	11.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.153% European (non-Finnish) · 1,810/1,179,620 alleles

Filtering AF 0.147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.119% 1,897/1,597,948 alleles · rare exomes 1,798/1,445,666 · genomes 99/152,282 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.153%	652
Remaining individualsnot grpmax-eligible	0.069%	1,449
Finnishnot grpmax-eligible	0.0329%	3,038
Admixed American	0.03%	3,331
African / African-American	0.0133%	7,505

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.Pro116=
Coding: c.348C>T
MANE Select: NM_005413
dbSNP: rs573768953
Type: single nucleotide variant
Location: chr2:44942452 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 116: 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 condition
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
SIX3 p.Gly317Ser 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-pro116 (accessed [today's date]).

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