Is SEC63 p.Val374Ile (c.1120G>A) pathogenic?

SEC63 p.Val374Ile (c.1120G>A) is classified Conflicting classifications of pathogenicity in SEC63 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-08-17). AlphaMissense: likely benign (0.1202); Ultra-rare (popmax 0.0213%, afr); Associated with Inborn genetic diseases.

What condition is associated with SEC63 p.Val374Ile (c.1120G>A)?

SEC63 p.Val374Ile (c.1120G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SEC63 p.Val374Ile (c.1120G>A) in the general population?

SEC63 p.Val374Ile (c.1120G>A) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

What do computational predictors say about SEC63 p.Val374Ile (c.1120G>A)?

AlphaMissense predicts likely benign (score 0.1202) — an in-silico prediction, not a clinical call.

SEC63 p.Val374Ile

c.1120G>A · rs577544394 · VCV729413

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1202 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1202	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -8.61	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 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 37 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	23.8	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 0.0213% African / African-American · 16/75,002 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00186% 30/1,613,722 alleles · ultra-rare exomes 20/1,461,540 · genomes 10/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0213%	4,688
South Asian	0.00439%	22,770
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
Admixed American	0.00167%	60,000
European (non-Finnish)	0.000678%	147,462

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.Val374Ile
Coding: c.1120G>A
MANE Select: NM_007214
dbSNP: rs577544394
Type: single nucleotide variant
Location: chr6:107902933 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 374: 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-val374ile (accessed [today's date]).

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