Is SORT1 p.Ser540= (c.1620C>T) pathogenic?

SORT1 p.Ser540= (c.1620C>T) is classified Benign in SORT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-09). Low-frequency (popmax 2.89%, sas); Associated with SORT1-related disorder.

What condition is associated with SORT1 p.Ser540= (c.1620C>T)?

SORT1 p.Ser540= (c.1620C>T) is associated with SORT1-related disorder (ClinVar).

How common is SORT1 p.Ser540= (c.1620C>T) in the general population?

SORT1 p.Ser540= (c.1620C>T) is low-frequency (popmax 2.89%, sas) (gnomAD).

SORT1 p.Ser540=

c.1620C>T · rs201347823 · VCV3045046

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.89%, sas)

Conditions

SORT1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Overall
CADD	13.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.89% South Asian · 2,631/90,968 alleles

Filtering AF 2.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.76%

Overall 0.175% 2,814/1,612,182 alleles · low-frequency exomes 2,658/1,459,896 · genomes 156/152,286 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.89%	35
Remaining individualsnot grpmax-eligible	0.22%	455
Middle Eastern	0.0861%	1,161
African / African-American	0.0187%	5,356
East Asian	0.00669%	14,957
Admixed American	0.00333%	29,999
European (non-Finnish)	0.00195%	51,297

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: SORT1
Protein: p.Ser540=
Coding: c.1620C>T
MANE Select: NM_002959
dbSNP: rs201347823
Type: single nucleotide variant
Location: chr1:109327015 (GRCh38)
Gene constraint: LOEUF 0.553 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 83.27 · 17 PDB
Residue 540: a β-strand; the '10-bladed beta-propeller' region; the vps10p domain

Full SORT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SORT1-related disorder

Similar variants

SORT1 c.544-5A>G Likely benign same condition
SORT1 p.Ile763= Likely benign same condition
SORT1 p.Phe198= Benign same condition
SORT1 p.Pro4= Benign same condition
SORT1 p.Pro747= Likely benign same condition
SORT1 p.Ser409= Likely benign same condition
SORT1 p.Thr323= Benign same condition
SORT1 p.Asp358Tyr Benign ★★ ⚠ 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/sort1-p-ser540 (accessed [today's date]).

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