Is SDF4 p.Arg196Ser (c.586C>A) pathogenic?

SDF4 p.Arg196Ser (c.586C>A) is classified Uncertain significance in SDF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.9616); Ultra-rare (popmax 0.0332%, mid).

How common is SDF4 p.Arg196Ser (c.586C>A) in the general population?

SDF4 p.Arg196Ser (c.586C>A) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about SDF4 p.Arg196Ser (c.586C>A)?

AlphaMissense predicts likely pathogenic (score 0.9616) — an in-silico prediction, not a clinical call.

SDF4 p.Arg196Ser

c.586C>A · VCV3951320

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9616	likely pathogenic · top 8% in SDF4
REVEL	0.46	indeterminate
SaProt	LLR -13.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.018 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R203S vs ClinVar R196S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,020 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000375% 6/1,600,018 alleles · ultra-rare exomes 6/1,447,722 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,010
Remaining individualsnot grpmax-eligible	0.00162%	61,812
European (non-Finnish)	0.000256%	390,383

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: SDF4
Protein: p.Arg196Ser
Coding: c.586C>A
MANE Select: NM_016176
Type: single nucleotide variant
Location: chr1:1218898 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.03
Residue 203 UniProt numbering: the ef-hand 3 domain

Full SDF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SDF4 p.Arg196Cys Uncertain significance ★ ⚠ same residue
SDF4 p.Ser35= Benign ★★ same type
SDF4 c.-11C>T Uncertain significance ★ ⚠ same type
SDF4 c.-18G>A Uncertain significance ★ ⚠ same type
SDF4 c.-3G>A Uncertain significance ★ ⚠ same type
SDF4 p.Ala161Val Uncertain significance ★ ⚠ same type
SDF4 p.Ala293Thr Uncertain significance ★ ⚠ same type
SDF4 p.Ala348Val 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/sdf4-p-arg196ser (accessed [today's date]).

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