Is SEC31A p.Pro168Ser (c.502C>T) pathogenic?

SEC31A p.Pro168Ser (c.502C>T) is classified Uncertain significance in SEC31A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-22). AlphaMissense: likely benign (0.0833); Very rare (popmax 0.00718%, amr).

How common is SEC31A p.Pro168Ser (c.502C>T) in the general population?

SEC31A p.Pro168Ser (c.502C>T) is very rare (popmax 0.00718%, amr) (gnomAD).

What do computational predictors say about SEC31A p.Pro168Ser (c.502C>T)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

SEC31A p.Pro168Ser

c.502C>T · VCV3439197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00718%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -8.54	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 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 63 kb · p 0.00023 · regional, not allelic
Overall
CADD	19.77	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 0.00718% Admixed American · 4/55,730 alleles

Filtering AF 0.00237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.000312% 5/1,602,176 alleles · very rare exomes 4/1,450,042 · genomes 1/152,134 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00718%	13,933
Remaining individualsnot grpmax-eligible	0.00161%	62,090

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: SEC31A
Protein: p.Pro168Ser
Coding: c.502C>T
MANE Select: NM_001077207
Type: single nucleotide variant
Location: chr4:82874748 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 68.95 · 2 PDB
Residue 168: the 'interaction with sec13' region

Full SEC31A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEC31A p.Arg486His Uncertain significance ★★ same type
SEC31A p.Asp84Gly Uncertain significance ★★ ⚠ same type
SEC31A p.Cys458Trp Uncertain significance ★★ ⚠ same type
SEC31A p.Pro945Ser Uncertain significance ★★ ⚠ same type
SEC31A c.1045-26G>T Benign ★★ same type
SEC31A c.2154+36G>C Benign ★★ same type
SEC31A c.2154+8C>T Likely benign ★★ same type
SEC31A c.2503-29C>A 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/sec31a-p-pro168ser (accessed [today's date]).

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