Is SCRIB p.Ala1516Thr (c.4546G>A) pathogenic?

SCRIB p.Ala1516Thr (c.4546G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.6687); Very rare (popmax 0.00554%, nfe).

How common is SCRIB p.Ala1516Thr (c.4546G>A) in the general population?

SCRIB p.Ala1516Thr (c.4546G>A) is very rare (popmax 0.00554%, nfe) (gnomAD).

What do computational predictors say about SCRIB p.Ala1516Thr (c.4546G>A)?

AlphaMissense predicts likely pathogenic (score 0.6687) — an in-silico prediction, not a clinical call.

SCRIB p.Ala1516Thr

c.4546G>A · rs781816612 · VCV2604335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00554%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6687	likely pathogenic
REVEL	0.352	indeterminate
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	25.8	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 0.00554% European (non-Finnish) · 65/1,174,304 alleles

Filtering AF 0.00445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00405%

Overall 0.00415% 66/1,588,712 alleles · very rare exomes 64/1,436,530 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00554%	18,066
Remaining individualsnot grpmax-eligible	0.00162%	61,806

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: SCRIB
Protein: p.Ala1516Thr
Coding: c.4546G>A
MANE Select: NM_182706
dbSNP: rs781816612
Type: single nucleotide variant
Location: chr8:143792102 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB

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

Similar variants

SCRIB c.3120+10C>G Benign/Likely benign ★★ same type
SCRIB c.504-9C>T Benign ★★ same type
SCRIB p.Ala1488= Likely benign ★★ same type
SCRIB p.Arg492= Benign ★★ same type
SCRIB p.Asn647= Benign/Likely benign ★★ same type
SCRIB p.Leu254= Benign ★★ same type
SCRIB p.Phe571= Benign ★★ same type
SCRIB p.Pro1343= Benign ★★ 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/scrib-p-ala1516thr (accessed [today's date]).

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