Is SGPL1 p.Pro565Ser (c.1693C>T) pathogenic?

SGPL1 p.Pro565Ser (c.1693C>T) is classified Benign/Likely benign in SGPL1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.094); Low-frequency (popmax 1.25%, afr).

How common is SGPL1 p.Pro565Ser (c.1693C>T) in the general population?

SGPL1 p.Pro565Ser (c.1693C>T) is low-frequency (popmax 1.25%, afr) (gnomAD).

What do computational predictors say about SGPL1 p.Pro565Ser (c.1693C>T)?

AlphaMissense predicts likely benign (score 0.094) — an in-silico prediction, not a clinical call.

SGPL1 p.Pro565Ser

c.1693C>T · rs77130902 · VCV715776

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.094 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.25%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.094	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 60 kb · p 7.1e-09 · regional, not allelic
Overall
CADD	17.26	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.25% African / African-American · 936/75,050 alleles

Filtering AF 1.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.15%

Overall 0.08% 1,292/1,614,192 alleles · low-frequency exomes 703/1,461,876 · genomes 589/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.25%	80
Middle Eastern	0.247%	404
Ashkenazi Jewishnot grpmax-eligible	0.23%	435
Remaining individualsnot grpmax-eligible	0.123%	812
Admixed American	0.095%	1,053
Finnishnot grpmax-eligible	0.0547%	1,830
European (non-Finnish)	0.00864%	11,569
South Asian	0.0022%	45,541

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: SGPL1
Protein: p.Pro565Ser
Coding: c.1693C>T
MANE Select: NM_003901
dbSNP: rs77130902
Type: single nucleotide variant
Location: chr10:70877321 (GRCh38)
Gene constraint: LOEUF 0.71 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07 · 2 PDB
Residue 565: a UniProt-annotated variant site (found in patients with atypical form of axonal peripheral neuropathy, characterized by acute or subacute onset and episodes of recurrent mononeuropathy; likely pathogenic); a UniProt-annotated variant site (in reni)

Full SGPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SGPL1 p.Arg222Gln Pathogenic ★★ same type
SGPL1 p.Arg495Ter Pathogenic ★★ same type
SGPL1 p.Arg505Ter Pathogenic ★★ same type
SGPL1 p.Tyr331Ter Pathogenic ★★ same type
SGPL1 p.Tyr416Cys Likely pathogenic ★★ same type
SGPL1 p.Ala316Thr Uncertain significance ★★ ⚠ same type
SGPL1 p.Ala492Ser Uncertain significance ★★ ⚠ same type
SGPL1 p.Arg278Gly 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/sgpl1-p-pro565ser (accessed [today's date]).

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