Is SIX5 p.Ala131Pro (c.391G>C) pathogenic?

SIX5 p.Ala131Pro (c.391G>C) is classified Uncertain significance in SIX5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1.

How common is SIX5 p.Ala131Pro (c.391G>C) in the general population?

SIX5 p.Ala131Pro (c.391G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX5 p.Ala131Pro (c.391G>C)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

SIX5 p.Ala131Pro

c.391G>C · rs1568565921 · VCV591605

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic · top 5% in SIX5
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -17.55	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 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	32.0	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: SIX5
Protein: p.Ala131Pro
Coding: c.391G>C
MANE Select: NM_175875
dbSNP: rs1568565921
Type: single nucleotide variant
Location: chr19:45768454 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21

Full SIX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX5 p.Ala408Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala649Ser Uncertain significance ★★ ⚠ same type
SIX5 p.Ala673Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala722Gly Uncertain significance ★★ ⚠ same type
SIX5 p.Asp698Glu 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/six5-p-ala131pro (accessed [today's date]).

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