Is SIX2 p.Val255Ala (c.764T>C) pathogenic?

SIX2 p.Val255Ala (c.764T>C) is classified Benign in SIX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1344); Rare (popmax 0.59%, afr).

How common is SIX2 p.Val255Ala (c.764T>C) in the general population?

SIX2 p.Val255Ala (c.764T>C) is rare (popmax 0.59%, afr) (gnomAD).

What do computational predictors say about SIX2 p.Val255Ala (c.764T>C)?

AlphaMissense predicts likely benign (score 0.1344) — an in-silico prediction, not a clinical call.

SIX2 p.Val255Ala

c.764T>C · rs140763514 · VCV2049063

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1344 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.59%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1344	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -7.64	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 11	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,568 bp · p 0.84 · regional, not allelic
Overall
CADD	22.0	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 0.59% African / African-American · 443/75,080 alleles

Filtering AF 0.545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.527%

Overall 0.0328% 530/1,614,132 alleles · rare exomes 291/1,461,760 · genomes 239/152,372 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.59%	169
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed American	0.04%	2,501
South Asian	0.00988%	10,120
European (non-Finnish)	0.00195%	51,303

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.Val255Ala
Coding: c.764T>C
MANE Select: NM_016932
dbSNP: rs140763514
Type: single nucleotide variant
Location: chr2:45006282 (GRCh38)
Gene constraint: LOEUF 1.24 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.99
Residue 255: the 'disordered' region

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

Similar variants

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.Pro258Leu 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-val255ala (accessed [today's date]).

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