Is SEC24D p.Pro181Ser (c.541C>T) pathogenic?

SEC24D p.Pro181Ser (c.541C>T) is classified Uncertain significance in SEC24D (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0748); Very rare (popmax 0.00167%, amr).

How common is SEC24D p.Pro181Ser (c.541C>T) in the general population?

SEC24D p.Pro181Ser (c.541C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SEC24D p.Pro181Ser (c.541C>T)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

SEC24D p.Pro181Ser

c.541C>T · rs1385815567 · VCV1363577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 110 kb · p 0.00018 · regional, not allelic
Overall
CADD	18.31	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 0.00167% Admixed American · 1/60,016 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,614,104 alleles · very rare exomes 16/1,461,892 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00144%	69,414

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.Pro181Ser
Coding: c.541C>T
MANE Select: NM_014822
dbSNP: rs1385815567
Type: single nucleotide variant
Location: chr4:118815583 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.21 · 6 PDB
Residue 181: the 'disordered' region

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

Similar variants

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
SEC24D p.Ala94Thr 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-pro181ser (accessed [today's date]).

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