Is SEC63 p.Pro637Ser (c.1909C>T) pathogenic?

SEC63 p.Pro637Ser (c.1909C>T) is classified Likely benign in SEC63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely benign (0.2612); Rare (popmax 0.101%, sas).

How common is SEC63 p.Pro637Ser (c.1909C>T) in the general population?

SEC63 p.Pro637Ser (c.1909C>T) is rare (popmax 0.101%, sas) (gnomAD).

What do computational predictors say about SEC63 p.Pro637Ser (c.1909C>T)?

AlphaMissense predicts likely benign (score 0.2612) — an in-silico prediction, not a clinical call.

SEC63 p.Pro637Ser

c.1909C>T · rs138273253 · VCV755540

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2612 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.101%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2612	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -7.56	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 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 37 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	22.2	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 0.101% South Asian · 92/91,002 alleles

Filtering AF 0.0843% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0782%

Overall 0.00695% 112/1,611,392 alleles · rare exomes 103/1,459,224 · genomes 9/152,168 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.101%	989
Middle Eastern	0.0187%	5,356
Remaining individualsnot grpmax-eligible	0.0144%	6,930
East Asian	0.00223%	44,820
African / African-American	0.00133%	74,926
European (non-Finnish)	0.000679%	147,312

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.Pro637Ser
Coding: c.1909C>T
MANE Select: NM_007214
dbSNP: rs138273253
Type: single nucleotide variant
Location: chr6:107881175 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 637: the sec63 2 domain; a UniProt-annotated variant site (in pcld2)

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

Similar variants

SEC63 p.Pro637Thr Uncertain significance ★ ⚠ same residue
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

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-pro637ser (accessed [today's date]).

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