Is DSCAML1 p.Ser535Phe (c.1604C>T) pathogenic?

DSCAML1 p.Ser535Phe (c.1604C>T) is classified Conflicting classifications of pathogenicity in DSCAML1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.7112); Very rare (popmax 0.00102%, nfe).

How common is DSCAML1 p.Ser535Phe (c.1604C>T) in the general population?

DSCAML1 p.Ser535Phe (c.1604C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about DSCAML1 p.Ser535Phe (c.1604C>T)?

AlphaMissense predicts likely pathogenic (score 0.7112) — an in-silico prediction, not a clinical call.

DSCAML1 p.Ser535Phe

c.1604C>T · rs148321554 · VCV2165565

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7112	likely pathogenic
REVEL	0.526	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 15 kb · p 4.3e-16 · regional, not allelic
Overall
CADD	27.7	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 0.00102% European (non-Finnish) · 12/1,180,012 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00731% 118/1,613,932 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.301%	333
Remaining individualsnot grpmax-eligible	0.0272%	3,676
European (non-Finnish)grpmax	0.00102%	98,334

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DSCAML1
Protein: p.Ser535Phe
Coding: c.1604C>T
MANE Select: NM_020693
dbSNP: rs148321554
Type: single nucleotide variant
Location: chr11:117516646 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.92 · 1 PDB
Residue 535: the ig-like c2-type 6 domain; a disulfide bond

Full DSCAML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DSCAML1 c.-101C>T Uncertain significance ★★ same type
DSCAML1 c.-17T>C Uncertain significance ★★ same type
DSCAML1 c.-23G>A Uncertain significance ★★ same type
DSCAML1 c.-44C>T Uncertain significance ★★ same type
DSCAML1 c.-51G>T Uncertain significance ★★ same type
DSCAML1 c.-57G>A Uncertain significance ★★ same type
DSCAML1 c.-87G>A Uncertain significance ★★ same type
DSCAML1 p.Ala1060Ser 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/dscaml1-p-ser535phe (accessed [today's date]).

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