Is SACS p.Ala2007Pro (c.6019G>C) pathogenic?

SACS p.Ala2007Pro (c.6019G>C) is classified Uncertain significance in SACS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely benign (0.2975); Very rare (popmax 6.2e-05%); Associated with Spastic paraplegia.

What condition is associated with SACS p.Ala2007Pro (c.6019G>C)?

SACS p.Ala2007Pro (c.6019G>C) is associated with Spastic paraplegia (ClinVar).

How common is SACS p.Ala2007Pro (c.6019G>C) in the general population?

SACS p.Ala2007Pro (c.6019G>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about SACS p.Ala2007Pro (c.6019G>C)?

AlphaMissense predicts likely benign (score 0.2975) — an in-silico prediction, not a clinical call.

SACS p.Ala2007Pro

c.6019G>C · rs1868794136 · VCV1978542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.2975	likely benign
REVEL	0.518	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 76 kb · p 0.00012 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,613,902 alleles · very rare exomes 1/1,461,610 · genomes 0/152,292 · joint denominator

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: SACS
Protein: p.Ala2007Pro
Coding: c.6019G>C
MANE Select: NM_014363
dbSNP: rs1868794136
Type: single nucleotide variant
Location: chr13:23337857 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SACS c.604+1G>A Likely pathogenic ★★ same condition
SACS p.Arg1877Ter Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg1907Ter Pathogenic ★★ same condition
SACS p.Arg2119Ter Pathogenic ★★ same condition
SACS p.Arg2425Ter Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg2426Ter Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg2703Cys Pathogenic/Likely pathogenic ★★ same condition
SACS p.Arg2906Ter Pathogenic/Likely pathogenic ★★ same condition

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/sacs-p-ala2007pro (accessed [today's date]).

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