Is SDC4 p.Ala8Val (c.23C>T) pathogenic?

SDC4 p.Ala8Val (c.23C>T) is classified Uncertain significance in SDC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely benign (0.2075); Very rare (popmax 0.00175%, amr).

How common is SDC4 p.Ala8Val (c.23C>T) in the general population?

SDC4 p.Ala8Val (c.23C>T) is very rare (popmax 0.00175%, amr) (gnomAD).

What do computational predictors say about SDC4 p.Ala8Val (c.23C>T)?

AlphaMissense predicts likely benign (score 0.2075) — an in-silico prediction, not a clinical call.

SDC4 p.Ala8Val

c.23C>T · VCV3951274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2075	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -4.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.48 · regional, not allelic
Overall
CADD	19.97	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% Admixed American · 1/57,252 alleles

Overall 6.29e-05% 1/1,591,004 alleles · very rare exomes 1/1,438,704 · genomes 0/152,300 · 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: SDC4
Protein: p.Ala8Val
Coding: c.23C>T
MANE Select: NM_002999
Type: single nucleotide variant
Location: chr20:45348362 (GRCh38)
Gene constraint: LOEUF 1.265 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.45 · 5 PDB

Full SDC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SDC4 p.Ala198Thr Uncertain significance ★ ⚠ same type
SDC4 p.Ala198Val Uncertain significance ★ ⚠ same type
SDC4 p.Arg171Cys Uncertain significance ★ ⚠ same type
SDC4 p.Arg171His Uncertain significance ★ ⚠ same type
SDC4 p.Arg22Gly Uncertain significance ★ ⚠ same type
SDC4 p.Arg5Cys Uncertain significance ★ ⚠ same type
SDC4 p.Arg92Gly Uncertain significance ★ ⚠ same type
SDC4 p.Asp181His Uncertain significance ★ 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/sdc4-p-ala8val (accessed [today's date]).

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