Is RALGAPB p.Pro1336Ser (c.4006C>T) pathogenic?

RALGAPB p.Pro1336Ser (c.4006C>T) is classified Benign in RALGAPB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.0991); Rare (popmax 0.78%, nfe); Associated with RALGAPB-related disorder.

What condition is associated with RALGAPB p.Pro1336Ser (c.4006C>T)?

RALGAPB p.Pro1336Ser (c.4006C>T) is associated with RALGAPB-related disorder (ClinVar).

How common is RALGAPB p.Pro1336Ser (c.4006C>T) in the general population?

RALGAPB p.Pro1336Ser (c.4006C>T) is rare (popmax 0.78%, nfe) (gnomAD).

What do computational predictors say about RALGAPB p.Pro1336Ser (c.4006C>T)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

RALGAPB p.Pro1336Ser

c.4006C>T · rs142678293 · VCV3043684

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.78%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RALGAPB-related disorder

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.385	indeterminate
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 7.4e-05 · regional, not allelic
Overall
CADD	24.2	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 0.78% European (non-Finnish) · 9,207/1,179,676 alleles

Filtering AF 0.767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.762%

Overall 0.631% 10,180/1,613,594 alleles · rare exomes 9,534/1,461,368 · genomes 646/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.78%	128
Ashkenazi Jewishnot grpmax-eligible	0.531%	188
Remaining individualsnot grpmax-eligible	0.467%	214
Finnishnot grpmax-eligible	0.358%	280
South Asian	0.147%	679
African / African-American	0.127%	789
Admixed American	0.103%	967
Middle Eastern	0.0495%	2,020
East Asian	0.00223%	44,880

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: RALGAPB
Protein: p.Pro1336Ser
Coding: c.4006C>T
MANE Select: NM_020336
dbSNP: rs142678293
Type: single nucleotide variant
Location: chr20:38569939 (GRCh38)
Gene constraint: LOEUF 0.202 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 75.28 · 1 PDB
Residue 1336: the rap-gap domain

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

Disease context

RALGAPB-related disorder

Similar variants

RALGAPB p.Pro271Ala Uncertain significance ★ ⚠ same condition
RALGAPB p.Val234= Uncertain significance ★ same condition
RALGAPB p.Lys84Arg Uncertain significance ⚠ same condition
RALGAPB c.554-10T>C Benign same condition
RALGAPB p.Ala998= Benign same condition
RALGAPB p.Asn276His Benign same condition
RALGAPB p.Asp1284= Benign same condition
RALGAPB p.Glu428= Benign 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/ralgapb-p-pro1336ser (accessed [today's date]).

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