Is SORT1 p.Ser814Phe (c.2441C>T) pathogenic?

SORT1 p.Ser814Phe (c.2441C>T) is classified Uncertain significance in SORT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.12); Very rare (popmax 0.000593%, nfe).

How common is SORT1 p.Ser814Phe (c.2441C>T) in the general population?

SORT1 p.Ser814Phe (c.2441C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about SORT1 p.Ser814Phe (c.2441C>T)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

SORT1 p.Ser814Phe

c.2441C>T · rs768499373 · VCV2252278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.11	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 9.9	GERP 2, 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

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 0.000593% European (non-Finnish) · 7/1,179,994 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,790 alleles · very rare exomes 5/1,461,834 · genomes 2/151,956 · 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: SORT1
Protein: p.Ser814Phe
Coding: c.2441C>T
MANE Select: NM_002959
dbSNP: rs768499373
Type: single nucleotide variant
Location: chr1:109314301 (GRCh38)
Gene constraint: LOEUF 0.553 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 83.27 · 17 PDB
Residue 814: the 'golgi to endosome transport and interactions with gga1 and gga2' region; a modified residue (phosphoserine)

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-ser814phe (accessed [today's date]).

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