Is SEC63 p.Leu34Phe (c.100C>T) pathogenic?

SEC63 p.Leu34Phe (c.100C>T) is classified Likely benign in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely benign (0.1624); Rare (popmax 0.283%, eas).

How common is SEC63 p.Leu34Phe (c.100C>T) in the general population?

SEC63 p.Leu34Phe (c.100C>T) is rare (popmax 0.283%, eas) (gnomAD).

What do computational predictors say about SEC63 p.Leu34Phe (c.100C>T)?

AlphaMissense predicts likely benign (score 0.1624) — an in-silico prediction, not a clinical call.

SEC63 p.Leu34Phe

c.100C>T · rs775021955 · VCV2908031

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1624 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.283%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1624	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 0.034 · regional, not allelic
Overall
CADD	22.8	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 0.283% East Asian · 127/44,818 alleles

Filtering AF 0.243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.228%

Overall 0.00887% 143/1,612,976 alleles · rare exomes 137/1,460,854 · genomes 6/152,122 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.283%	353
Remaining individualsnot grpmax-eligible	0.00801%	12,487
South Asian	0.00329%	30,361
Admixed American	0.00167%	59,986
European (non-Finnish)	0.000594%	168,489

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.Leu34Phe
Coding: c.100C>T
MANE Select: NM_007214
dbSNP: rs775021955
Type: single nucleotide variant
Location: chr6:107957910 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 34: a UniProt-annotated variant site (in pcld2)

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

Similar variants

SEC63 c.452+1G>A Pathogenic/Likely pathogenic ★★ same type
SEC63 c.625-2A>G Likely pathogenic ★★ same type
SEC63 c.733+1G>A Pathogenic ★★ same type
SEC63 p.Arg239Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Arg622Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Arg98Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Ser632Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Trp58Ter Pathogenic ★★ 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/sec63-p-leu34phe (accessed [today's date]).

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