Is SEC63 p.Phe86Leu (c.258C>A) pathogenic?

SEC63 p.Phe86Leu (c.258C>A) is classified Likely benign in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely pathogenic (0.7811); Ultra-rare (popmax 0.014%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SEC63 p.Phe86Leu (c.258C>A)?

SEC63 p.Phe86Leu (c.258C>A) is associated with Inborn genetic diseases (ClinVar).

How common is SEC63 p.Phe86Leu (c.258C>A) in the general population?

SEC63 p.Phe86Leu (c.258C>A) is ultra-rare (popmax 0.014%, nfe) (gnomAD).

What do computational predictors say about SEC63 p.Phe86Leu (c.258C>A)?

AlphaMissense predicts likely pathogenic (score 0.7811) — an in-silico prediction, not a clinical call.

SEC63 p.Phe86Leu

c.258C>A · VCV3951879

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7811	likely pathogenic
REVEL	0.136	moderately benign-leaning
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP -1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 0.034 · regional, not allelic
Overall
CADD	14.6	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 0.014% European (non-Finnish) · 164/1,168,380 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0104% 166/1,600,946 alleles · ultra-rare exomes 162/1,448,774 · genomes 4/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.014%	7,124
Remaining individualsnot grpmax-eligible	0.00323%	30,996

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.Phe86Leu
Coding: c.258C>A
MANE Select: NM_007214
Type: single nucleotide variant
Location: chr6:107924899 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 86: a UniProt-annotated variant site (in pcld2)

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-phe86leu (accessed [today's date]).

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