Is SEC24D p.Ser1015Phe (c.3044C>T) pathogenic?

SEC24D p.Ser1015Phe (c.3044C>T) is classified Pathogenic in SEC24D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-23). AlphaMissense: likely pathogenic (0.941); Very rare (popmax 0.00017%, nfe); Associated with Cole-Carpenter syndrome 2.

What condition is associated with SEC24D p.Ser1015Phe (c.3044C>T)?

SEC24D p.Ser1015Phe (c.3044C>T) is associated with Cole-Carpenter syndrome 2 (ClinVar).

How common is SEC24D p.Ser1015Phe (c.3044C>T) in the general population?

SEC24D p.Ser1015Phe (c.3044C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SEC24D p.Ser1015Phe (c.3044C>T)?

AlphaMissense predicts likely pathogenic (score 0.941) — an in-silico prediction, not a clinical call.

SEC24D p.Ser1015Phe

c.3044C>T · rs760670617 · VCV189339

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cole-Carpenter syndrome 2

Computational evidence

Protein change
AlphaMissense	0.941	likely pathogenic ✓ concordant with ClinVar
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, 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 0.00017% European (non-Finnish) · 2/1,179,856 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,776 alleles · very rare exomes 2/1,461,670 · genomes 0/152,106 · 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.Ser1015Phe
Coding: c.3044C>T
MANE Select: NM_014822
dbSNP: rs760670617
Type: single nucleotide variant
Location: chr4:118723570 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.21 · 6 PDB
Residue 1015: a UniProt-annotated variant site (in clcrp2)

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.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
SEC24D c.2093-14T>C Likely benign ★★ same condition
SEC24D c.2959-16G>T 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-ser1015phe (accessed [today's date]).

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