Is SEC23A p.Ala478Pro (c.1432G>C) pathogenic?

SEC23A p.Ala478Pro (c.1432G>C) is classified Uncertain significance in SEC23A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely pathogenic (0.9651); Very rare (popmax 6.2e-05%).

How common is SEC23A p.Ala478Pro (c.1432G>C) in the general population?

SEC23A p.Ala478Pro (c.1432G>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about SEC23A p.Ala478Pro (c.1432G>C)?

AlphaMissense predicts likely pathogenic (score 0.9651) — an in-silico prediction, not a clinical call.

SEC23A p.Ala478Pro

c.1432G>C · rs759091967 · VCV3159242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9651	likely pathogenic
REVEL	0.58	indeterminate
SaProt	LLR -5.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 0.001 · regional, not allelic
Overall
CADD	27.6	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 6.2e-05%

Overall 6.2e-05% 1/1,613,966 alleles · very rare exomes 1/1,461,666 · genomes 0/152,300 · 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: SEC23A
Protein: p.Ala478Pro
Coding: c.1432G>C
MANE Select: NM_006364
dbSNP: rs759091967
Type: single nucleotide variant
Location: chr14:39061838 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.86 · 38 PDB
Residue 478: a β-strand

Full SEC23A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEC23A p.Ala478Ser Uncertain significance ★★ ⚠ same residue
SEC23A p.Ala284Pro Uncertain significance ★★ ⚠ same type
SEC23A p.Arg123Cys Uncertain significance ★★ ⚠ same type
SEC23A p.Arg476His Uncertain significance ★★ ⚠ same type
SEC23A p.Arg67His Uncertain significance ★★ ⚠ same type
SEC23A p.Arg716Cys Uncertain significance ★★ ⚠ same type
SEC23A p.Asn680Asp Uncertain significance ★★ ⚠ same type
SEC23A p.Cys180Tyr 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/sec23a-p-ala478pro (accessed [today's date]).

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