Is CYP7B1 p.Ala26Val (c.77C>T) pathogenic?

CYP7B1 p.Ala26Val (c.77C>T) is classified Uncertain significance in CYP7B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: likely benign (0.1768); Very rare (popmax 0.0015%, nfe); Associated with Spastic paraplegia.

What condition is associated with CYP7B1 p.Ala26Val (c.77C>T)?

CYP7B1 p.Ala26Val (c.77C>T) is associated with Spastic paraplegia (ClinVar).

How common is CYP7B1 p.Ala26Val (c.77C>T) in the general population?

CYP7B1 p.Ala26Val (c.77C>T) is very rare (popmax 0.0015%, nfe) (gnomAD).

What do computational predictors say about CYP7B1 p.Ala26Val (c.77C>T)?

AlphaMissense predicts likely benign (score 0.1768) — an in-silico prediction, not a clinical call.

CYP7B1 p.Ala26Val

c.77C>T · rs754214163 · VCV458231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0015%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1768	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	GERP -2, phastCons 0.001
Regional constraint	o/e 1.09	unconstrained · MANE · 202 kb · p 0.026 · regional, not allelic
Overall
CADD	16.28	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0015% European (non-Finnish) · 17/1,136,910 alleles

Filtering AF 0.000911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000745%

Overall 0.00113% 17/1,507,492 alleles · very rare exomes 17/1,355,192 · genomes 0/152,300 · 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: CYP7B1
Protein: p.Ala26Val
Coding: c.77C>T
MANE Select: NM_004820
dbSNP: rs754214163
Type: single nucleotide variant
Location: chr8:64798511 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.98

Full CYP7B1 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

CYP7B1 p.Ala26= Likely benign ★ same residue
CYP7B1 c.1233+1G>A Pathogenic/Likely pathogenic ★★ same condition
CYP7B1 c.259+2T>C Pathogenic/Likely pathogenic ★★ same condition
CYP7B1 c.260-1G>A Pathogenic/Likely pathogenic ★★ same condition
CYP7B1 p.Arg388Ter Pathogenic ★★ same condition
CYP7B1 p.Arg417Cys Pathogenic/Likely pathogenic ★★ same condition
CYP7B1 p.Arg452Ter Pathogenic/Likely pathogenic ★★ same condition
CYP7B1 p.Trp175Ter 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/cyp7b1-p-ala26val (accessed [today's date]).

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