Is SCRIB p.Glu1611Lys (c.4831G>A) pathogenic?

SCRIB p.Glu1611Lys (c.4831G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely benign (0.1739); Ultra-rare (popmax 0.0117%, sas).

How common is SCRIB p.Glu1611Lys (c.4831G>A) in the general population?

SCRIB p.Glu1611Lys (c.4831G>A) is ultra-rare (popmax 0.0117%, sas) (gnomAD).

What do computational predictors say about SCRIB p.Glu1611Lys (c.4831G>A)?

AlphaMissense predicts likely benign (score 0.1739) — an in-silico prediction, not a clinical call.

SCRIB p.Glu1611Lys

c.4831G>A · VCV3793346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1739	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 0.46, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E1586K vs ClinVar E1611K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% South Asian · 10/85,758 alleles

Filtering AF 0.00628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00478%

Overall 0.000704% 11/1,563,436 alleles · ultra-rare exomes 10/1,411,228 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0117%	8,576
European (non-Finnish)	8.66e-05%	1,154,303

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.Glu1611Lys
Coding: c.4831G>A
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143791300 (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-glu1611lys (accessed [today's date]).

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