Is SIX3 p.Asp205His (c.613G>C) pathogenic?

SIX3 p.Asp205His (c.613G>C) is classified Uncertain significance in SIX3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-03). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 8.48e-05%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Asp205His (c.613G>C)?

SIX3 p.Asp205His (c.613G>C) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Asp205His (c.613G>C) in the general population?

SIX3 p.Asp205His (c.613G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SIX3 p.Asp205His (c.613G>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

SIX3 p.Asp205His

c.613G>C · rs886044000 · VCV288767

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 2

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -14.82	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 2.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 435 bp · p 5.9e-10 · regional, not allelic
Overall
CADD	35.0	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 8.48e-05% European (non-Finnish) · 1/1,179,834 alleles

Overall 0.000657% 1/152,228 alleles · very rare

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.Asp205His
Coding: c.613G>C
MANE Select: NM_005413
dbSNP: rs886044000
Type: single nucleotide variant
Location: chr2:44942717 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38

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.Gly103Arg Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly317Ser Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly43Cys 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-asp205his (accessed [today's date]).

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