Is SEC24D p.Pro320Leu (c.959C>T) pathogenic?

SEC24D p.Pro320Leu (c.959C>T) is classified Uncertain significance in SEC24D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-08). AlphaMissense: likely pathogenic (0.8664); Absent from gnomAD v4.1.

How common is SEC24D p.Pro320Leu (c.959C>T) in the general population?

SEC24D p.Pro320Leu (c.959C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SEC24D p.Pro320Leu (c.959C>T)?

AlphaMissense predicts likely pathogenic (score 0.8664) — an in-silico prediction, not a clinical call.

SEC24D p.Pro320Leu

c.959C>T · VCV3655163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8664 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8664	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -11.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 110 kb · p 0.00018 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: SEC24D
Protein: p.Pro320Leu
Coding: c.959C>T
MANE Select: NM_014822
Type: single nucleotide variant
Location: chr4:118797765 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.21 · 6 PDB
Residue 320: a β-strand

Full SEC24D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEC24D p.Pro320Ser Likely pathogenic same residue
SEC24D c.1181-1G>C Likely pathogenic ★★ same type
SEC24D c.1824+1G>T Likely pathogenic ★★ same type
SEC24D p.Arg993Ter Pathogenic/Likely pathogenic ★★ same type
SEC24D p.Ser1015Phe Pathogenic ★★ same type
SEC24D p.Ala218Val Uncertain significance ★★ ⚠ same type
SEC24D p.Ala570Val Uncertain significance ★★ ⚠ same type
SEC24D p.Ala774Asp 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/sec24d-p-pro320leu (accessed [today's date]).

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