Is SEC24D p.Pro437Ser (c.1309C>T) pathogenic?

SEC24D p.Pro437Ser (c.1309C>T) is classified Uncertain significance in SEC24D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.2726); Very rare (popmax 0.00938%, afr).

How common is SEC24D p.Pro437Ser (c.1309C>T) in the general population?

SEC24D p.Pro437Ser (c.1309C>T) is very rare (popmax 0.00938%, afr) (gnomAD).

What do computational predictors say about SEC24D p.Pro437Ser (c.1309C>T)?

AlphaMissense predicts likely benign (score 0.2726) — an in-silico prediction, not a clinical call.

SEC24D p.Pro437Ser

c.1309C>T · VCV4686361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00938%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2726	likely benign
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -10.76	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 110 kb · p 0.00018 · regional, not allelic
Overall
CADD	27.5	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 0.00938% African / African-American · 7/74,608 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.000497% 8/1,608,996 alleles · very rare exomes 3/1,456,896 · genomes 5/152,100 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00938%	10,658
East Asian	0.00224%	44,722

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.Pro437Ser
Coding: c.1309C>T
MANE Select: NM_014822
Type: single nucleotide variant
Location: chr4:118757833 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.21 · 6 PDB
Residue 437: an α-helix

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

Similar variants

SEC24D p.Pro437= Likely benign ★ 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-pro437ser (accessed [today's date]).

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