Is RASGRP1 p.Ala57Ser (c.169G>T) pathogenic?

RASGRP1 p.Ala57Ser (c.169G>T) is classified Uncertain significance in RASGRP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-02). AlphaMissense: likely benign (0.0971); Ultra-rare (popmax 0.099%, mid).

How common is RASGRP1 p.Ala57Ser (c.169G>T) in the general population?

RASGRP1 p.Ala57Ser (c.169G>T) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about RASGRP1 p.Ala57Ser (c.169G>T)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

RASGRP1 p.Ala57Ser

c.169G>T · rs769304356 · VCV1524120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -5.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.69, phastCons 0.93
Regional constraint	o/e 0.73	unconstrained · MANE · 63 kb · p 9.6e-13 · regional, not allelic
Overall
CADD	15.43	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.00192% 31/1,613,982 alleles · ultra-rare exomes 27/1,461,680 · genomes 4/152,302 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00195%	51,299

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: RASGRP1
Protein: p.Ala57Ser
Coding: c.169G>T
MANE Select: NM_005739
dbSNP: rs769304356
Type: single nucleotide variant
Location: chr15:38559872 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 72.43 · 2 PDB
Residue 57: the n-terminal ras-gef domain; the 'ras exchanger motif region; required for transforming activity' region

Full RASGRP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RASGRP1 p.Ala57= Likely benign ★ same residue
RASGRP1 c.327-1C>G Pathogenic/Likely pathogenic ★★ same type
RASGRP1 p.Arg81Ter Pathogenic/Likely pathogenic ★★ same type
RASGRP1 p.Arg167Cys Uncertain significance ★★ ⚠ same type
RASGRP1 p.Arg177His Uncertain significance ★★ ⚠ same type
RASGRP1 p.Arg663Gln Uncertain significance ★★ ⚠ same type
RASGRP1 p.Arg741His Uncertain significance ★★ ⚠ same type
RASGRP1 p.Asn241Ser Uncertain significance ★★ ⚠ same type

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/rasgrp1-p-ala57ser (accessed [today's date]).

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