Is SRRM2 p.Ser692Phe (c.2075C>T) pathogenic?

SRRM2 p.Ser692Phe (c.2075C>T) is classified Uncertain significance in SRRM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-31). AlphaMissense: likely pathogenic (0.7167); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with SRRM2 p.Ser692Phe (c.2075C>T)?

SRRM2 p.Ser692Phe (c.2075C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SRRM2 p.Ser692Phe (c.2075C>T) in the general population?

SRRM2 p.Ser692Phe (c.2075C>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about SRRM2 p.Ser692Phe (c.2075C>T)?

AlphaMissense predicts likely pathogenic (score 0.7167) — an in-silico prediction, not a clinical call.

SRRM2 p.Ser692Phe

c.2075C>T · VCV3449548

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7167 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7167	likely pathogenic
REVEL	0.169	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 3.6, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 11 kb · p 1.5e-90 · regional, not allelic
Overall
CADD	24.9	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 0.01% Admixed American · 6/60,008 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000496% 8/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,088

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.Ser692Phe
Coding: c.2075C>T
MANE Select: NM_016333
Type: single nucleotide variant
Location: chr16:2762603 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 692: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SRRM2 p.Ser692Cys Uncertain significance ★ same residue
SRRM2 p.Arg1836Ter Pathogenic ★★ same condition
SRRM2 p.Arg280Ter Pathogenic ★★ same condition
SRRM2 p.Ala2245Val Uncertain significance ★★ same condition
SRRM2 p.Arg1213Gly Uncertain significance ★★ ⚠ same condition
SRRM2 p.Arg1723Lys Uncertain significance ★★ ⚠ same condition
SRRM2 p.Arg1971Gln Uncertain significance ★★ same condition
SRRM2 p.Arg530Gln 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-ser692phe (accessed [today's date]).

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