Is GPD2 p.Ser616Pro (c.1846T>C) pathogenic?

GPD2 p.Ser616Pro (c.1846T>C) is classified Uncertain significance in GPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.2076); Very rare (popmax 0.00333%, amr).

How common is GPD2 p.Ser616Pro (c.1846T>C) in the general population?

GPD2 p.Ser616Pro (c.1846T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about GPD2 p.Ser616Pro (c.1846T>C)?

AlphaMissense predicts likely benign (score 0.2076) — an in-silico prediction, not a clinical call.

GPD2 p.Ser616Pro

c.1846T>C · rs765878694 · VCV2409320

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2076	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -6.75	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 1.6	GERP -1.1, phastCons 0.99
Regional constraint	o/e 0.85	unconstrained · MANE · 104 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	17.82	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 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,457,674 alleles · very rare

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: GPD2
Protein: p.Ser616Pro
Coding: c.1846T>C
MANE Select: NM_000408
dbSNP: rs765878694
Type: single nucleotide variant
Location: chr2:156578967 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.47

Full GPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPD2 p.Asn224Lys Uncertain significance ★★ ⚠ same type
GPD2 p.Ile308Val Likely benign ★★ same type
GPD2 c.497+5G>A Uncertain significance ★ same type
GPD2 p.Ala233Pro Uncertain significance ★ ⚠ same type
GPD2 p.Ala305Thr Uncertain significance ★ ⚠ same type
GPD2 p.Ala499Thr Conflicting classifications of pathogenicity ★ ⚠ same type
GPD2 p.Ala512Ser Uncertain significance ★ ⚠ same type
GPD2 p.Ala565Ser 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/gpd2-p-ser616pro (accessed [today's date]).

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