Is SEC24C p.Ser181Pro (c.541T>C) pathogenic?

SEC24C p.Ser181Pro (c.541T>C) is classified Uncertain significance in SEC24C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0911); Very rare (popmax 0.000509%, nfe).

How common is SEC24C p.Ser181Pro (c.541T>C) in the general population?

SEC24C p.Ser181Pro (c.541T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about SEC24C p.Ser181Pro (c.541T>C)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

SEC24C p.Ser181Pro

c.541T>C · VCV4161772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -7.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP -0.46, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 14 kb · p 0.5 · regional, not allelic
Overall
CADD	19.64	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 0.000509% European (non-Finnish) · 6/1,178,558 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,612,122 alleles · very rare exomes 4/1,460,112 · genomes 2/152,010 · 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.Ser181Pro
Coding: c.541T>C
MANE Select: NM_198597
Type: single nucleotide variant
Location: chr10:73760077 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.29 · 3 PDB
Residue 181: the 'disordered' region

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

Similar variants

SEC24C p.Ser181Cys Uncertain significance ★ ⚠ same residue
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

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-ser181pro (accessed [today's date]).

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