Is SEC63 p.Pro258Ser (c.772C>T) pathogenic?

SEC63 p.Pro258Ser (c.772C>T) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-20). AlphaMissense: ambiguous (0.3615); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SEC63 p.Pro258Ser (c.772C>T)?

SEC63 p.Pro258Ser (c.772C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SEC63 p.Pro258Ser (c.772C>T) in the general population?

SEC63 p.Pro258Ser (c.772C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SEC63 p.Pro258Ser (c.772C>T)?

AlphaMissense predicts ambiguous (score 0.3615) — an in-silico prediction, not a clinical call.

SEC63 p.Pro258Ser

c.772C>T · VCV3317173

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3615 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3615	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 37 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	23.6	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 8.48e-05% European (non-Finnish) · 1/1,179,910 alleles

Overall 6.2e-05% 1/1,613,746 alleles · very rare exomes 1/1,461,696 · genomes 0/152,050 · 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: SEC63
Protein: p.Pro258Ser
Coding: c.772C>T
MANE Select: NM_007214
Type: single nucleotide variant
Location: chr6:107906739 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 258: a UniProt-annotated variant site (in pcld2); the sec63 1 domain

Full SEC63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEC63 p.Ala497Thr Uncertain significance ★★ ⚠ same condition
SEC63 p.Arg98Gln Uncertain significance ★★ ⚠ same condition
SEC63 p.Asn349Asp Uncertain significance ★★ ⚠ same condition
SEC63 p.His389Leu Uncertain significance ★★ same condition
SEC63 p.His717Arg Uncertain significance ★★ ⚠ same condition
SEC63 p.Leu191Pro Uncertain significance ★★ ⚠ same condition
SEC63 p.Leu532Phe Uncertain significance ★★ ⚠ same condition
SEC63 p.Lys328Met Uncertain significance ★★ ⚠ same condition

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/sec63-p-pro258ser (accessed [today's date]).

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