Is SEC24C p.His643Arg (c.1928A>G) pathogenic?

SEC24C p.His643Arg (c.1928A>G) is classified Uncertain significance in SEC24C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-10). AlphaMissense: likely pathogenic (0.9628); Very rare (popmax 8.48e-05%, nfe).

How common is SEC24C p.His643Arg (c.1928A>G) in the general population?

SEC24C p.His643Arg (c.1928A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SEC24C p.His643Arg (c.1928A>G)?

AlphaMissense predicts likely pathogenic (score 0.9628) — an in-silico prediction, not a clinical call.

SEC24C p.His643Arg

c.1928A>G · VCV3439169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9628	likely pathogenic
REVEL	0.72	pathogenic-leaning
SaProt	LLR -11.41	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 1.3e-13 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,920 alleles

Overall 6.2e-05% 1/1,614,028 alleles · very rare exomes 1/1,461,714 · genomes 0/152,314 · 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: SEC24C
Protein: p.His643Arg
Coding: c.1928A>G
MANE Select: NM_198597
Type: single nucleotide variant
Location: chr10:73767088 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.29 · 3 PDB
Residue 643: a β-strand

Full SEC24C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEC24C c.1800-7T>C Benign ★★ same type
SEC24C c.3145-4G>A Benign ★★ same type
SEC24C c.850+10T>G Benign ★★ same type
SEC24C p.Ala566= Benign ★★ same type
SEC24C p.Gly257= Benign/Likely benign ★★ same type
SEC24C p.Pro255Ala Benign ★★ same type
SEC24C p.Pro958= Likely benign ★★ same type
SEC24C p.Thr870= Likely benign ★★ 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/sec24c-p-his643arg (accessed [today's date]).

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