Is GRAMD1A p.Pro558Ser (c.1672C>T) pathogenic?

GRAMD1A p.Pro558Ser (c.1672C>T) is classified Uncertain significance in GRAMD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.1163); Very rare (popmax 8.48e-05%, nfe).

How common is GRAMD1A p.Pro558Ser (c.1672C>T) in the general population?

GRAMD1A p.Pro558Ser (c.1672C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about GRAMD1A p.Pro558Ser (c.1672C>T)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

GRAMD1A p.Pro558Ser

c.1672C>T · VCV3522397

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -4.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 13 kb · p 0.00017 · regional, not allelic
Overall
CADD	23.2	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 8.48e-05% European (non-Finnish) · 1/1,179,332 alleles

Overall 6.2e-05% 1/1,611,974 alleles · very rare exomes 1/1,459,650 · genomes 0/152,324 · joint denominator

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: GRAMD1A
Protein: p.Pro558Ser
Coding: c.1672C>T
MANE Select: NM_020895
Type: single nucleotide variant
Location: chr19:35021783 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.70

Full GRAMD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRAMD1A p.Ala283Val Uncertain significance ★ ⚠ same type
GRAMD1A p.Ala315Val Uncertain significance ★ ⚠ same type
GRAMD1A p.Ala380Thr Uncertain significance ★ ⚠ same type
GRAMD1A p.Ala438Val Uncertain significance ★ ⚠ same type
GRAMD1A p.Ala563Asp Uncertain significance ★ ⚠ same type
GRAMD1A p.Ala650Ser Uncertain significance ★ ⚠ same type
GRAMD1A p.Ala668Val Uncertain significance ★ ⚠ same type
GRAMD1A p.Arg10Trp 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/gramd1a-p-pro558ser (accessed [today's date]).

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