Is SEC24D p.Pro320Ser (c.958C>T) pathogenic?

SEC24D p.Pro320Ser (c.958C>T) is classified Likely pathogenic in SEC24D (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.8919); Very rare (popmax 0.00441%, sas); Associated with Cole-Carpenter syndrome 2.

What condition is associated with SEC24D p.Pro320Ser (c.958C>T)?

SEC24D p.Pro320Ser (c.958C>T) is associated with Cole-Carpenter syndrome 2 (ClinVar).

How common is SEC24D p.Pro320Ser (c.958C>T) in the general population?

SEC24D p.Pro320Ser (c.958C>T) is very rare (popmax 0.00441%, sas) (gnomAD).

What do computational predictors say about SEC24D p.Pro320Ser (c.958C>T)?

AlphaMissense predicts likely pathogenic (score 0.8919) — an in-silico prediction, not a clinical call.

SEC24D p.Pro320Ser

c.958C>T · rs2530206539 · VCV3242255

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cole-Carpenter syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8919	likely pathogenic ✓ concordant with ClinVar
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -11.20	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	27.2	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

Grpmax group 0.00441% South Asian · 4/90,744 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000894%

Overall 0.000248% 4/1,611,390 alleles · very rare exomes 4/1,459,138 · genomes 0/152,252 · 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: SEC24D
Protein: p.Pro320Ser
Coding: c.958C>T
MANE Select: NM_014822
dbSNP: rs2530206539
Type: single nucleotide variant
Location: chr4:118797766 (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

Disease context

Cole-Carpenter syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEC24D p.Pro320Leu Uncertain significance ★ ⚠ same residue
SEC24D p.Ser1015Phe Pathogenic ★★ same condition
SEC24D p.Arg912Cys Uncertain significance ★★ ⚠ same condition
SEC24D p.Asp597Val Uncertain significance ★★ same condition
SEC24D p.Gly233Arg Uncertain significance ★★ ⚠ same condition
SEC24D p.Gly241Val Uncertain significance ★★ ⚠ same condition
SEC24D p.Pro261Ser Uncertain significance ★★ same condition
SEC24D c.1042-6C>G Benign/Likely benign ★★ same condition

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-pro320ser (accessed [today's date]).

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