Is SORT1 p.Ser409= (c.1227C>T) pathogenic?

SORT1 p.Ser409= (c.1227C>T) is classified Likely benign in SORT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-12-06). Rare (popmax 0.181%, mid); Associated with SORT1-related disorder.

What condition is associated with SORT1 p.Ser409= (c.1227C>T)?

SORT1 p.Ser409= (c.1227C>T) is associated with SORT1-related disorder (ClinVar).

How common is SORT1 p.Ser409= (c.1227C>T) in the general population?

SORT1 p.Ser409= (c.1227C>T) is rare (popmax 0.181%, mid) (gnomAD).

SORT1 p.Ser409=

c.1227C>T · rs746387781 · VCV3047969

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.181%, mid)

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 3	GERP 0.86, phastCons 1
Overall
CADD	11.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.181% Middle Eastern · 11/6,084 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0784%

Overall 0.0164% 264/1,614,020 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.181%	553
European (non-Finnish)	0.0196%	5,108
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Admixed American	0.01%	10,000
South Asian	0.00439%	22,770
African / African-American	0.004%	24,972

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.Ser409=
Coding: c.1227C>T
MANE Select: NM_002959
dbSNP: rs746387781
Type: single nucleotide variant
Location: chr1:109340761 (GRCh38)
Gene constraint: LOEUF 0.553 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 83.27 · 17 PDB
Residue 409: the '10-bladed beta-propeller' region; a disulfide bond; the vps10p domain; a β-strand

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.Ser540= 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-ser409 (accessed [today's date]).

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