Is SIX3 p.Glu76Val (c.227A>T) pathogenic?

SIX3 p.Glu76Val (c.227A>T) is classified Uncertain significance in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: ambiguous (0.3658); Very rare (popmax 0.0028%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Glu76Val (c.227A>T)?

SIX3 p.Glu76Val (c.227A>T) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Glu76Val (c.227A>T) in the general population?

SIX3 p.Glu76Val (c.227A>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about SIX3 p.Glu76Val (c.227A>T)?

AlphaMissense predicts ambiguous (score 0.3658) — an in-silico prediction, not a clinical call.

SIX3 p.Glu76Val

c.227A>T · rs770543339 · VCV1498282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

holoprosencephaly 2

Computational evidence

Protein change
AlphaMissense	0.3658	ambiguous
REVEL	0.284	benign-leaning
SaProt	LLR -5.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 230 bp · p 0.3 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,178,476 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00213% 34/1,594,974 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,711
Remaining individualsnot grpmax-eligible	0.00161%	62,126

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.Glu76Val
Coding: c.227A>T
MANE Select: NM_005413
dbSNP: rs770543339
Type: single nucleotide variant
Location: chr2:44942331 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 76: 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.Glu76Lys Uncertain significance ★ same residue
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

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-glu76val (accessed [today's date]).

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