Is SIX3 p.Ala20Ser (c.58G>T) pathogenic?

SIX3 p.Ala20Ser (c.58G>T) is classified Benign in SIX3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.079); Rare (popmax 0.313%, sas); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Ala20Ser (c.58G>T)?

SIX3 p.Ala20Ser (c.58G>T) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Ala20Ser (c.58G>T) in the general population?

SIX3 p.Ala20Ser (c.58G>T) is rare (popmax 0.313%, sas) (gnomAD).

What do computational predictors say about SIX3 p.Ala20Ser (c.58G>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

SIX3 p.Ala20Ser

c.58G>T · rs200575650 · VCV707261

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.313%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 2

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.28, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 230 bp · p 0.3 · regional, not allelic
Overall
CADD	20.8	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 0.313% South Asian · 285/91,004 alleles

Filtering AF 0.283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.272%

Overall 0.0205% 327/1,598,064 alleles · rare exomes 313/1,446,384 · genomes 14/151,680 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.313%	319
Remaining individualsnot grpmax-eligible	0.0305%	3,279
African / African-American	0.00267%	37,415
European (non-Finnish)	0.00178%	56,161

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.Ala20Ser
Coding: c.58G>T
MANE Select: NM_005413
dbSNP: rs200575650
Type: single nucleotide variant
Location: chr2:44942162 (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.Ala20= Likely benign ★ 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-ala20ser (accessed [today's date]).

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