Is SRRM2 p.Pro399Ser (c.1195C>T) pathogenic?

SRRM2 p.Pro399Ser (c.1195C>T) is classified Likely benign in SRRM2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-27). AlphaMissense: likely benign (0.105); Very rare (popmax 0.00773%, nfe); Associated with SRRM2-related disorder.

What condition is associated with SRRM2 p.Pro399Ser (c.1195C>T)?

SRRM2 p.Pro399Ser (c.1195C>T) is associated with SRRM2-related disorder (ClinVar).

How common is SRRM2 p.Pro399Ser (c.1195C>T) in the general population?

SRRM2 p.Pro399Ser (c.1195C>T) is very rare (popmax 0.00773%, nfe) (gnomAD).

What do computational predictors say about SRRM2 p.Pro399Ser (c.1195C>T)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

SRRM2 p.Pro399Ser

c.1195C>T · rs201759902 · VCV3032062

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00773%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

SRRM2-related disorder

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.186	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 3.6, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 11 kb · p 1.5e-90 · regional, not allelic
Overall
CADD	22.7	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 0.00773% European (non-Finnish) · 91/1,177,446 alleles

Filtering AF 0.00641% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.0141% 227/1,608,956 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.194%	514
Remaining individualsnot grpmax-eligible	0.0193%	5,189
European (non-Finnish)grpmax	0.00773%	12,939

Finnish 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: SRRM2
Protein: p.Pro399Ser
Coding: c.1195C>T
MANE Select: NM_016333
dbSNP: rs201759902
Type: single nucleotide variant
Location: chr16:2761723 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 399: the 'disordered' region; 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 disorder

Similar variants

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
SRRM2 p.Arg668Ser 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-pro399ser (accessed [today's date]).

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