Is CLGN p.Ser554Gly (c.1660A>G) pathogenic?

CLGN p.Ser554Gly (c.1660A>G) is classified Likely benign in CLGN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-27). AlphaMissense: likely benign (0.0507); Ultra-rare (popmax 0.016%, nfe).

How common is CLGN p.Ser554Gly (c.1660A>G) in the general population?

CLGN p.Ser554Gly (c.1660A>G) is ultra-rare (popmax 0.016%, nfe) (gnomAD).

What do computational predictors say about CLGN p.Ser554Gly (c.1660A>G)?

AlphaMissense predicts likely benign (score 0.0507) — an in-silico prediction, not a clinical call.

CLGN p.Ser554Gly

c.1660A>G · rs145828622 · VCV2521246

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0507 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0507	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -7.26	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 1.7	GERP 2.8, phastCons 0.9
Regional constraint	o/e 0.90	unconstrained · MANE · 24 kb · p 0.01 · regional, not allelic
Overall
CADD	10.47	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% European (non-Finnish) · 187/1,171,384 alleles

Filtering AF 0.014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0134%

Overall 0.0122% 195/1,599,354 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.016%	6,264
Remaining individualsnot grpmax-eligible	0.0097%	10,313
African / African-American	0.00134%	74,488
South Asian	0.00112%	89,350

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: CLGN
Protein: p.Ser554Gly
Coding: c.1660A>G
MANE Select: NM_004362
dbSNP: rs145828622
Type: single nucleotide variant
Location: chr4:140390720 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.36
Residue 554: the 'disordered' region

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

Similar variants

CLGN p.Ala210Thr Uncertain significance ★ ⚠ same type
CLGN p.Ala529Thr Uncertain significance ★ ⚠ same type
CLGN p.Ala63Gly Uncertain significance ★ ⚠ same type
CLGN p.Arg196Gly Uncertain significance ★ ⚠ same type
CLGN p.Arg373Ser Uncertain significance ★ ⚠ same type
CLGN p.Arg603His Uncertain significance ★ ⚠ same type
CLGN p.Arg608Gln Uncertain significance ★ ⚠ same type
CLGN p.Arg70Thr 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/clgn-p-ser554gly (accessed [today's date]).

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