Is SRRM2 p.Ser1069Cys (c.3206C>G) pathogenic?

SRRM2 p.Ser1069Cys (c.3206C>G) is classified Uncertain significance in SRRM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.1138); Very rare (popmax 0.000339%, nfe); Associated with SRRM2-related Neurodevelopmental disorder.

What condition is associated with SRRM2 p.Ser1069Cys (c.3206C>G)?

SRRM2 p.Ser1069Cys (c.3206C>G) is associated with SRRM2-related Neurodevelopmental disorder (ClinVar).

How common is SRRM2 p.Ser1069Cys (c.3206C>G) in the general population?

SRRM2 p.Ser1069Cys (c.3206C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SRRM2 p.Ser1069Cys (c.3206C>G)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

SRRM2 p.Ser1069Cys

c.3206C>G · rs1199295504 · VCV1696541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

SRRM2-related Neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.3	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 3.4, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 11 kb · p 1.5e-90 · regional, not allelic
Overall
CADD	17.81	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,036 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,182 alleles · very rare exomes 4/1,461,864 · genomes 0/152,318 · 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: SRRM2
Protein: p.Ser1069Cys
Coding: c.3206C>G
MANE Select: NM_016333
dbSNP: rs1199295504
Type: single nucleotide variant
Location: chr16:2763734 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1069: the 'disordered' region; a modified residue (phosphoserine); a UniProt-annotated variant site (in mrd72; likely pathogenic)

Full SRRM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SRRM2-related Neurodevelopmental disorder

Similar variants

SRRM2 p.Ser1069Pro Uncertain significance ★ ⚠ same residue
SRRM2 p.Arg628Ter Pathogenic ★★ same condition
SRRM2 p.Thr499Ala Uncertain significance ★★ ⚠ same condition
SRRM2 p.Arg507Ter Pathogenic ★ same condition
SRRM2 p.Arg699Ter Pathogenic ★ same condition
SRRM2 p.Gln1002Ter Likely pathogenic ★ same condition
SRRM2 p.Ser838Ter Pathogenic ★ same condition
SRRM2 p.Arg2384Ser Uncertain significance ★ same condition

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/srrm2-p-ser1069cys (accessed [today's date]).

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