Is ADD1 p.Leu555Val (c.1663T>G) pathogenic?

ADD1 p.Leu555Val (c.1663T>G) is classified Uncertain significance in ADD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-12). AlphaMissense: likely pathogenic (0.7177); Ultra-rare (popmax 0.0427%, nfe).

How common is ADD1 p.Leu555Val (c.1663T>G) in the general population?

ADD1 p.Leu555Val (c.1663T>G) is ultra-rare (popmax 0.0427%, nfe) (gnomAD).

What do computational predictors say about ADD1 p.Leu555Val (c.1663T>G)?

AlphaMissense predicts likely pathogenic (score 0.7177) — an in-silico prediction, not a clinical call.

ADD1 p.Leu555Val

c.1663T>G · VCV4832294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7177 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7177	likely pathogenic
REVEL	0.495	indeterminate
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61	GERP -2.9
Regional constraint	o/e 0.93	unconstrained · MANE · 53 kb · p 0.026 · regional, not allelic
Overall
CADD	19.23	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L524V vs ClinVar L555V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0427% European (non-Finnish) · 504/1,179,562 alleles

Filtering AF 0.0396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.038% 555/1,461,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0427%	2,340
Remaining individualsnot grpmax-eligible	0.0336%	2,976
African / African-American	0.02%	5,000
Middle Eastern	0.0165%	6,060
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
South Asian	0.00988%	10,118
Admixed American	0.00333%	30,012

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.Leu555Val
Coding: c.1663T>G
MANE Select: NM_001354761
Type: single nucleotide variant
Location: chr4:2908569 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.73

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

Similar variants

ADD1 p.Leu555Trp Uncertain significance ★ ⚠ same residue
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

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-leu555val (accessed [today's date]).

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