Is CLGN p.Met585Thr (c.1754T>C) pathogenic?

CLGN p.Met585Thr (c.1754T>C) is classified Uncertain significance in CLGN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely benign (0.2939); Very rare (popmax 0.00484%, nfe).

How common is CLGN p.Met585Thr (c.1754T>C) in the general population?

CLGN p.Met585Thr (c.1754T>C) is very rare (popmax 0.00484%, nfe) (gnomAD).

What do computational predictors say about CLGN p.Met585Thr (c.1754T>C)?

AlphaMissense predicts likely benign (score 0.2939) — an in-silico prediction, not a clinical call.

CLGN p.Met585Thr

c.1754T>C · VCV3493628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00484%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2939	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -4.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.68 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 6.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 24 kb · p 0.01 · 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 0.00484% European (non-Finnish) · 57/1,177,894 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.0036% 58/1,610,800 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00484%	20,665
African / African-American	0.00134%	74,814

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.Met585Thr
Coding: c.1754T>C
MANE Select: NM_004362
Type: single nucleotide variant
Location: chr4:140389303 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.36
Residue 585: 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-met585thr (accessed [today's date]).

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