Is SIX1 p.Ser48Arg (c.144C>G) pathogenic?

SIX1 p.Ser48Arg (c.144C>G) is classified Uncertain significance in SIX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-03). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1.

How common is SIX1 p.Ser48Arg (c.144C>G) in the general population?

SIX1 p.Ser48Arg (c.144C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX1 p.Ser48Arg (c.144C>G)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

SIX1 p.Ser48Arg

c.144C>G · VCV4755876

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -16.07	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 1.3	GERP 0.31, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 306 bp · p 0.92 · regional, not allelic
Overall
CADD	23.5	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

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: SIX1
Protein: p.Ser48Arg
Coding: c.144C>G
MANE Select: NM_005982
Type: single nucleotide variant
Location: chr14:60649046 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB
Residue 48: an α-helix

Full SIX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX1 p.Ser48= Likely benign ★ same residue
SIX1 p.Arg110Gln Pathogenic/Likely pathogenic ★★ same type
SIX1 p.Arg110Trp Pathogenic ★★ same type
SIX1 p.Glu125Lys Pathogenic/Likely pathogenic ★★ same type
SIX1 p.Tyr129Cys Pathogenic ★★ same type
SIX1 p.Val106Met Likely pathogenic ★★ same type
SIX1 p.Ala184Thr Uncertain significance ★★ same type
SIX1 p.Arg119His 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/six1-p-ser48arg (accessed [today's date]).

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