Is SEC23B p.Phe576Val (c.1726T>G) pathogenic?

SEC23B p.Phe576Val (c.1726T>G) is classified Uncertain significance in SEC23B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-01). AlphaMissense: ambiguous (0.3877); Very rare (popmax 0.000266%, nfe).

How common is SEC23B p.Phe576Val (c.1726T>G) in the general population?

SEC23B p.Phe576Val (c.1726T>G) is very rare (popmax 0.000266%, nfe) (gnomAD).

What do computational predictors say about SEC23B p.Phe576Val (c.1726T>G)?

AlphaMissense predicts ambiguous (score 0.3877) — an in-silico prediction, not a clinical call.

SEC23B p.Phe576Val

c.1726T>G · rs2517508282 · VCV2689938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000266%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3877	ambiguous
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -13.20	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 50 kb · p 0.036 · regional, not allelic
Overall
CADD	26.7	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 0.000266% European (non-Finnish) · 3/1,129,290 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000192% 3/1,558,490 alleles · very rare exomes 3/1,406,140 · genomes 0/152,350 · 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: SEC23B
Protein: p.Phe576Val
Coding: c.1726T>G
MANE Select: NM_006363
dbSNP: rs2517508282
Type: single nucleotide variant
Location: chr20:18546016 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.41
Residue 576: a UniProt-annotated variant site (in cdan2)

Full SEC23B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEC23B c.1314+1G>A Likely pathogenic ★★ same type
SEC23B c.835-2A>G Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Ala524Val Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Arg14Trp Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Arg264Ter Pathogenic ★★ same type
SEC23B p.Arg313His Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Arg324Ter Pathogenic/Likely pathogenic ★★ same type
SEC23B p.Arg339Ter 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/sec23b-p-phe576val (accessed [today's date]).

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