Is SEC24D p.Arg993Ter (c.2977C>T) pathogenic?

SEC24D p.Arg993Ter (c.2977C>T) is classified Pathogenic/Likely pathogenic in SEC24D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-22). Very rare (popmax 0.00223%, eas); Associated with SEC24D-related disorder.

What condition is associated with SEC24D p.Arg993Ter (c.2977C>T)?

SEC24D p.Arg993Ter (c.2977C>T) is associated with SEC24D-related disorder (ClinVar).

How common is SEC24D p.Arg993Ter (c.2977C>T) in the general population?

SEC24D p.Arg993Ter (c.2977C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

SEC24D p.Arg993Ter

c.2977C>T · rs769202646 · VCV2003692

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

SEC24D-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (23 of 23) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.41	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.4	GERP -2.3, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,846 alleles

Overall 6.21e-05% 1/1,611,334 alleles · very rare exomes 1/1,459,430 · genomes 0/151,904 · 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.Arg993Ter
Coding: c.2977C>T
MANE Select: NM_014822
dbSNP: rs769202646
Type: single nucleotide variant
Location: chr4:118723637 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.21 · 6 PDB

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

Disease context

SEC24D-related disorder

Similar variants

SEC24D p.Arg993Gln Uncertain significance ★★ ⚠ same residue
SEC24D c.1181-1G>C Likely pathogenic ★★ same condition
SEC24D p.Ala284= Likely benign same condition
SEC24D p.Leu601= Likely benign same condition
SEC24D p.Tyr1016= Likely benign same condition
SEC24D p.Thr702fs Likely pathogenic ★ same condition
SEC24D c.1824+1G>T Likely pathogenic ★★ same type
SEC24D p.Ser1015Phe Pathogenic ★★ 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-arg993ter (accessed [today's date]).

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