Is SORT1 p.Phe139Ser (c.416T>C) pathogenic?

SORT1 p.Phe139Ser (c.416T>C) is classified Uncertain significance in SORT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.7097); Absent from gnomAD v4.1.

How common is SORT1 p.Phe139Ser (c.416T>C) in the general population?

SORT1 p.Phe139Ser (c.416T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SORT1 p.Phe139Ser (c.416T>C)?

AlphaMissense predicts likely pathogenic (score 0.7097) — an in-silico prediction, not a clinical call.

SORT1 p.Phe139Ser

c.416T>C · VCV4587888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7097 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7097	likely pathogenic
REVEL	0.175	moderately benign-leaning
SaProt	LLR -4.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.4	GERP 0.59, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 84 kb · p 1.9e-12 · regional, not allelic
Overall
CADD	23.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SORT1
Protein: p.Phe139Ser
Coding: c.416T>C
MANE Select: NM_002959
Type: single nucleotide variant
Location: chr1:109367432 (GRCh38)
Gene constraint: LOEUF 0.553 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 83.27 · 17 PDB
Residue 139: the '10-bladed beta-propeller' region; the vps10p domain

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

Similar variants

SORT1 p.Asp358Tyr Benign ★★ ⚠ same type
SORT1 p.Ser746Asn Benign ★★ same type
SORT1 p.Ala340Thr Uncertain significance ★ ⚠ same type
SORT1 p.Arg288Lys Uncertain significance ★ ⚠ same type
SORT1 p.Arg311His Uncertain significance ★ ⚠ same type
SORT1 p.Arg326Ser Uncertain significance ★ ⚠ same type
SORT1 p.Arg382Gln Uncertain significance ★ ⚠ same type
SORT1 p.Arg392Leu 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/sort1-p-phe139ser (accessed [today's date]).

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