Is SEC23A p.Pro96Ser (c.286C>T) pathogenic?

SEC23A p.Pro96Ser (c.286C>T) is classified Uncertain significance in SEC23A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.22); Very rare (popmax 0.000426%, nfe).

How common is SEC23A p.Pro96Ser (c.286C>T) in the general population?

SEC23A p.Pro96Ser (c.286C>T) is very rare (popmax 0.000426%, nfe) (gnomAD).

What do computational predictors say about SEC23A p.Pro96Ser (c.286C>T)?

AlphaMissense predicts likely benign (score 0.22) — an in-silico prediction, not a clinical call.

SEC23A p.Pro96Ser

c.286C>T · VCV3439102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.22 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000426%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.22	likely benign
REVEL	0.495	indeterminate
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 0.001 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000426% European (non-Finnish) · 5/1,173,290 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000312% 5/1,604,538 alleles · very rare exomes 5/1,452,298 · genomes 0/152,240 · 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.Pro96Ser
Coding: c.286C>T
MANE Select: NM_006364
Type: single nucleotide variant
Location: chr14:39092621 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.86 · 38 PDB
Residue 96: an α-helix

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

Similar variants

SEC23A p.Ala284Pro Uncertain significance ★★ ⚠ same type
SEC23A p.Ala478Ser 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-pro96ser (accessed [today's date]).

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