Is SIX2 p.Ser242Phe (c.725C>T) pathogenic?

SIX2 p.Ser242Phe (c.725C>T) is classified Uncertain significance in SIX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-01). AlphaMissense: likely benign (0.1752); Absent from gnomAD v4.1.

How common is SIX2 p.Ser242Phe (c.725C>T) in the general population?

SIX2 p.Ser242Phe (c.725C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX2 p.Ser242Phe (c.725C>T)?

AlphaMissense predicts likely benign (score 0.1752) — an in-silico prediction, not a clinical call.

SIX2 p.Ser242Phe

c.725C>T · VCV3772022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1752 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1752	likely benign
REVEL	0.389	indeterminate
SaProt	LLR -10.04	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,568 bp · p 0.84 · regional, not allelic
Overall
CADD	23.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SIX2
Protein: p.Ser242Phe
Coding: c.725C>T
MANE Select: NM_016932
Type: single nucleotide variant
Location: chr2:45006321 (GRCh38)
Gene constraint: LOEUF 1.24 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.99
Residue 242: the 'disordered' region

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

Similar variants

SIX2 p.Ser242Cys Uncertain significance ★ ⚠ 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.Pro258Leu 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-ser242phe (accessed [today's date]).

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