Is OBSL1 p.Pro993Ser (c.2977C>T) pathogenic?

OBSL1 p.Pro993Ser (c.2977C>T) is classified Uncertain significance in OBSL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.8644); Very rare (popmax 0.0011%, sas); Associated with 3M syndrome 2.

What condition is associated with OBSL1 p.Pro993Ser (c.2977C>T)?

OBSL1 p.Pro993Ser (c.2977C>T) is associated with 3M syndrome 2 (ClinVar).

How common is OBSL1 p.Pro993Ser (c.2977C>T) in the general population?

OBSL1 p.Pro993Ser (c.2977C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about OBSL1 p.Pro993Ser (c.2977C>T)?

AlphaMissense predicts likely pathogenic (score 0.8644) — an in-silico prediction, not a clinical call.

OBSL1 p.Pro993Ser

c.2977C>T · rs1292400698 · VCV896129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3M syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8644	likely pathogenic
REVEL	0.274	benign-leaning
SaProt	LLR -15.02	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.69 · regional, not allelic
Overall
CADD	20.4	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 0.0011% South Asian · 1/91,052 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,612 alleles · very rare exomes 6/1,461,562 · genomes 1/152,050 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,052
European (non-Finnish)	0.000509%	196,625

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: OBSL1
Protein: p.Pro993Ser
Coding: c.2977C>T
MANE Select: NM_015311
dbSNP: rs1292400698
Type: single nucleotide variant
Location: chr2:219559474 (GRCh38)
Gene constraint: LOEUF 1.212 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.74 · 10 PDB
Residue 993: the ig-like 8 domain

Full OBSL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3M syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OBSL1 p.Gln678Ter Pathogenic ★★ same condition
OBSL1 c.4610-6G>A Uncertain significance ★★ same condition
OBSL1 c.-209C>G Uncertain significance ★★ same condition
OBSL1 c.-51A>C Uncertain significance ★★ same condition
OBSL1 p.Ala706Pro Uncertain significance ★★ ⚠ same condition
OBSL1 p.Ala90Thr Uncertain significance ★★ ⚠ same condition
OBSL1 p.Arg1043Cys Uncertain significance ★★ ⚠ same condition
OBSL1 p.Arg1098Cys 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/obsl1-p-pro993ser (accessed [today's date]).

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