Is SEC24D p.Glu423Asp (c.1269A>C) pathogenic?

SEC24D p.Glu423Asp (c.1269A>C) is classified Uncertain significance in SEC24D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-26). AlphaMissense: likely pathogenic (0.5988); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with SEC24D p.Glu423Asp (c.1269A>C)?

SEC24D p.Glu423Asp (c.1269A>C) is associated with Inborn genetic diseases (ClinVar).

How common is SEC24D p.Glu423Asp (c.1269A>C) in the general population?

SEC24D p.Glu423Asp (c.1269A>C) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about SEC24D p.Glu423Asp (c.1269A>C)?

AlphaMissense predicts likely pathogenic (score 0.5988) — an in-silico prediction, not a clinical call.

SEC24D p.Glu423Asp

c.1269A>C · rs368390247 · VCV2074506

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5988 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5988	likely pathogenic
REVEL	0.251	benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.48	GERP -3.7, phastCons 0.13
Regional constraint	o/e 0.89	unconstrained · MANE · 110 kb · p 0.00018 · regional, not allelic
Overall
CADD	22.2	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 0.0107% African / African-American · 8/74,668 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00287% 46/1,603,758 alleles · ultra-rare exomes 39/1,451,542 · genomes 7/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,333
Remaining individualsnot grpmax-eligible	0.00644%	15,540
Admixed American	0.00333%	29,990
European (non-Finnish)	0.00273%	36,597

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.Glu423Asp
Coding: c.1269A>C
MANE Select: NM_014822
dbSNP: rs368390247
Type: single nucleotide variant
Location: chr4:118764829 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.21 · 6 PDB
Residue 423: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEC24D c.1824+1G>T Likely pathogenic ★★ same condition
SEC24D p.Ala218Val Uncertain significance ★★ ⚠ same condition
SEC24D p.Ala570Val Uncertain significance ★★ ⚠ same condition
SEC24D p.Ala774Asp Uncertain significance ★★ ⚠ same condition
SEC24D p.Ala94Thr Uncertain significance ★★ ⚠ same condition
SEC24D p.Arg365Thr Uncertain significance ★★ ⚠ same condition
SEC24D p.Asp1018Asn Uncertain significance ★★ ⚠ same condition
SEC24D p.Asp429Tyr Uncertain significance ★★ ⚠ 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-glu423asp (accessed [today's date]).

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