Is SIX2 p.Pro258Leu (c.773C>T) pathogenic?

SIX2 p.Pro258Leu (c.773C>T) is classified Uncertain significance in SIX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-21). AlphaMissense: likely benign (0.1206); Ultra-rare (popmax 0.0167%, amr).

How common is SIX2 p.Pro258Leu (c.773C>T) in the general population?

SIX2 p.Pro258Leu (c.773C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about SIX2 p.Pro258Leu (c.773C>T)?

AlphaMissense predicts likely benign (score 0.1206) — an in-silico prediction, not a clinical call.

SIX2 p.Pro258Leu

c.773C>T · rs373961258 · VCV2185533

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1206 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1206	likely benign
REVEL	0.419	indeterminate
SaProt	LLR -8.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,568 bp · p 0.84 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0167% Admixed American · 10/60,012 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00322% 52/1,614,034 alleles · ultra-rare exomes 49/1,461,794 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,001
East Asian	0.00891%	11,223
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.00297%	33,714
South Asian	0.0011%	91,086

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: SIX2
Protein: p.Pro258Leu
Coding: c.773C>T
MANE Select: NM_016932
dbSNP: rs373961258
Type: single nucleotide variant
Location: chr2:45006273 (GRCh38)
Gene constraint: LOEUF 1.24 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.99
Residue 258: the 'disordered' region

Full SIX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX2 p.Pro258= Likely benign ★★ same residue
SIX2 p.Asn280Ser Uncertain significance ★★ ⚠ same type
SIX2 p.Gly220Val Uncertain significance ★★ ⚠ same type
SIX2 p.Gly261Ser Uncertain significance ★★ ⚠ same type
SIX2 p.Pro235Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Pro236Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Pro250Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Ser212Trp Uncertain significance ★★ ⚠ same type

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/six2-p-pro258leu (accessed [today's date]).

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