Is ADD1 p.Pro673Ser (c.2017C>T) pathogenic?

ADD1 p.Pro673Ser (c.2017C>T) is classified Uncertain significance in ADD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-27). AlphaMissense: likely benign (0.0969); Very rare (popmax 0.00508%, nfe).

How common is ADD1 p.Pro673Ser (c.2017C>T) in the general population?

ADD1 p.Pro673Ser (c.2017C>T) is very rare (popmax 0.00508%, nfe) (gnomAD).

What do computational predictors say about ADD1 p.Pro673Ser (c.2017C>T)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

ADD1 p.Pro673Ser

c.2017C>T · VCV3269860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.44	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 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 53 kb · p 0.026 · regional, not allelic
Overall
CADD	23.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P611S vs ClinVar P673S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00508% European (non-Finnish) · 60/1,180,024 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00397% 64/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00508%	19,667
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Admixed American	0.00167%	60,006
Finnishnot grpmax-eligible	0.00156%	64,040

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: ADD1
Protein: p.Pro673Ser
Coding: c.2017C>T
MANE Select: NM_001354761
Type: single nucleotide variant
Location: chr4:2926082 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.73
Residue 673: the 'disordered' region

Full ADD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADD1 p.Val234= Benign ★★ same type
ADD1 p.Val559Met Benign ★★ same type
ADD1 c.2047+530G>A Uncertain significance ★ same type
ADD1 c.2047+541G>T Uncertain significance ★ same type
ADD1 p.Ala137Val Uncertain significance ★ ⚠ same type
ADD1 p.Ala151Thr Uncertain significance ★ ⚠ same type
ADD1 p.Ala156Thr Uncertain significance ★ ⚠ same type
ADD1 p.Ala18Thr 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/add1-p-pro673ser (accessed [today's date]).

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