Is SACS p.Ile1426Val (c.4276A>G) pathogenic?

SACS p.Ile1426Val (c.4276A>G) is classified Conflicting classifications of pathogenicity in SACS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-22). AlphaMissense: likely benign (0.1884); Ultra-rare (popmax 0.0174%, afr); Associated with Spastic paraplegia.

What condition is associated with SACS p.Ile1426Val (c.4276A>G)?

SACS p.Ile1426Val (c.4276A>G) is associated with Spastic paraplegia (ClinVar).

How common is SACS p.Ile1426Val (c.4276A>G) in the general population?

SACS p.Ile1426Val (c.4276A>G) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about SACS p.Ile1426Val (c.4276A>G)?

AlphaMissense predicts likely benign (score 0.1884) — an in-silico prediction, not a clinical call.

SACS p.Ile1426Val

c.4276A>G · rs771667607 · VCV2157259

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1884	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 76 kb · p 0.00012 · regional, not allelic
Overall
CADD	22.5	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 0.0174% African / African-American · 13/74,892 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000992% 16/1,612,306 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,761
South Asian	0.0011%	90,976
European (non-Finnish)	0.00017%	589,345

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.Ile1426Val
Coding: c.4276A>G
MANE Select: NM_014363
dbSNP: rs771667607
Type: single nucleotide variant
Location: chr13:23339600 (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-ile1426val (accessed [today's date]).

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